Devices and methods for treating defects in the tissue of a living being

ABSTRACT

An implant for deployment in select locations or select tissue for regeneration of tissue is disclosed. The implant comprising collagen and or other bio-resorbable materials, where the implant may also be used for therapy delivery. Additionally, the implant may be “matched” to provide the implant with similar physical and/or chemical properties as the host tissue.

RELATED APPLICATION CROSS REFERENCE

[0001] The present application is a continuation of U.S. patentapplication Ser. No. 10/171,248, filed Jun. 13, 2002, which is assignedto the same assignee as this invention and whose disclosure is fullyincorporated by reference herein.

BACKGROUND OF THE INVENTION

[0002] This invention relates generally to medical devices andprocedures and more particularly to devices and methods for treatingdefects in the tissue of a living being.

[0003] To better treat our aging population, physicians are looking fornew and better products and methods to enhance the body's own mechanismto produce rapid healing of musculoskeletal injuries and degenerativediseases. Treatment of these defects has traditionally relied upon thenatural ability of these types of tissue to repair themselves. In manyinstances the body is unable to repair such defects in a reasonabletime, if at all. Advances in biomaterials has allowed for the creationof devices to facilitate wound healing in both bone and soft tissuesdefects and injuries. Such devices are used in tissue regeneration astissue (e.g. bone) graft scaffolds, for use in trauma and spinalapplications, and for the delivery of drugs and growth factors.

[0004] Bone and soft tissue repair is necessary to treat a variety ofmedical (e.g. orthopedic) conditions. For example, when hard tissue suchas bone is damaged as a result of disease or injury, it is oftennecessary to provide an implant or graft to augment the damaged boneduring the healing process to prevent further damage and stimulaterepair. Such implants may take many forms (e.g. plugs, putties, rods,dowels, wedges, screws, plates, etc.) which are placed into the tissue.Typically, such implants can be rigid, flexible, deformable, or flowableand can be prepared in a variety of shapes and sizes. For rigid implants(e.g. bone screws), the defect site is typically preconditioned byforming a depression, channel, or other feature (e.g. pre-tapped hole)therein in preparation for the application of the implant. For non-rigidstructural repair materials (e.g. putties and pastes) to be convenientlyused, they must be capable of being formed into a variety of complexshapes to fit the contours of the repair site. An accurately configuredimplant that substantially fills the defect site will enhance theintegration of natural bone and tissue to provide better healing overtime. For example, when repairing defects in bone, intimate loadcarrying contact often is desired between the natural bone and the bonesubstitute material to promote bone remodeling and regeneration leadingto incorporation of the graft by host bone.

[0005] Current bone graft materials include autografts (the use of bonefrom the patient), allografts (the use of cadaver bone), and a varietyof other artificial or synthetic bone substitute materials. Autograftsare typically comprised of cancellous bone and/or cortical bone.Cancellous bone grafts essentially provide minimal structural integrity.Bone strength increases as the implant incorporates surrounding cellsand new bone is deposited. For cortical bone, the graft initiallyprovides some structural strength. However, as the graft is incorporatedby the host bone, nonviable bone is removed by resorption significantlyreducing the strength of the graft. The use of autograft bone may resultin severe patient pain and other complications at the harvest site, andthere are limitations to the amount of autograft bone that can beharvested from the patient. Allografts are similar to autografts in thatthey are comprised of cancellous and/or cortical bone with greaterquantities and sizes being typically available. Disadvantages ofallografts include limited supplies of materials and the potential fortransmission of disease. The disadvantages of the existing productscreates a need for a better devices and methods for treating defects inthe tissue of a living being.

[0006] Collagen is the most abundant protein found in the body. Theunique chemistry of collagen makes it an ideal material for structuraland hemostatic applications in both clinical and diagnostic settings.Collagen, like all proteins, is comprised of amino acids linkedcovalently through peptide or amide linkages. The sequence of the aminoacids, or the primary structure, outlines the three-dimensionalstructure of the protein which in turn dictates the function andCollagen has been used in a number of applications in the art. Forexample, one application is for use in hemostatic devices for thestoppage of bleeding, such as is described in U.S. Pat. Nos. 5,310,407(Casal) and 4,890,612 (Kensey). However, neither teaches the use ofnative insoluble fibrous collagen. In U.S. Pat. No. 5,425,769, Snyders,Jr. discloses a biocompatible and bioresorbable bone substitute withphysical and chemical properties similar to bone, consisting ofreconstituted fibrillar collagen within a calcium sulfate di-hydratematrix. The ratios of calcium sulfate and collagen are adjusted for eachapplication and the bone substitute is molded in situ to form a solidphase. Similarly, U.S. Pat. No. 5,425,770 (Piez, et. al.) discloses acomposition made from a calcium phosphate particulate mineral such ashydroxyapatite or tricalcium phosphate mixed with atelopeptidereconstituted fibrillar collagen for conductive bone repair. U.S. Pat.No. 5,904,718, (Jefferies) describes a process and invention comprisingdemineralized bone particles and collagen. Examples of medical implantsthat utilize reconstituted fibrous collagen include U.S. Pat. Nos.4,642,117 (Nguyen , et al. ), 4,795,467 (Piez , et al. ), and 5,997,896(Carr, et al. ). The '718, '769 and '770 patents, all require the use ofreconstituted collagen.

[0007] U.S. Pat. Nos. 4,563,350 and 4,888,366 describe the use oflyophilized and preformed collagen carriers of osteoinductive factors inbone repair, respectively. When used as preformed solid implants, thesecarriers consist generally of ceramic materials which are held togetherby collagen. Similarly, U.S. Pat. No. 4,776,890 describesnon-crosslinked collagen/mineral implants, which can be moistened andmolded into a desired shape before implantation. Therein, crosslinkingis described as being undesirable because of its inhibitory effects onbone in-growth. U.S. Pat. Nos. 4,795,467, 5,035,715 and 5,110,604describe porous collagen-containing implants for use in bone repairand/or wound healing. U.S. Pat. No 4,948,540 (Nigam) describes a type offibrous native collagen for use as a hemostatic dressing. Thesereferences do not teach or suggest the solution to the ubiquitousproblem of high porosity and excessive resilience in acollagen-containing implant material for bone defect repair.

[0008] Devices made from compressed collagen matrices include Robinsonet al. (Cardiovasc Intervent Radiol 1990; 13:36-39), who described theuse of compressed collagen plugs prepared from Gelfoam™ (manufactured byPharmacia & Upjohn Company, Kalamazoo, Mich.) to repair biopsy tractdefects in lungs. Armstrong et al. (Arch Dermatol 1986; 122:546-549)described the use of compressed collagen plugs prepared from Helistat™(manufactured by Integra LifeSciences) to repair cutaneous biopsywounds. All of these references teach the use of collagen but none teachthe use of the multi-phasic composition of the present invention,furthermore the function of these devices is for stopping the bleedingfrom a puncture and not for regenerating tissue.

[0009] Accordingly, a need remains for a defect filling material,prepared primarily of collagen, which has improved mechanical stabilityand is adequately dense and sufficiently conformable for medical orsurgical utility.

[0010] U.S. Pat. No. 6,110,484 (Sierra) describes an implant formed insitu, that contains a biodegradable porosifying agent; however theembodiment is a pre-formed solid plug and porosity is not rapidlycreated following implanting, to form an osteoconductive structure.Therefore, a need exists for an implant that rapidly becomes porousfollowing implantation.

[0011] Various embodiments of these devices include polysaccharides inthe construct. Polysaccharides are a key component of the extracellularmatrix component of bone and related tissue, since they providehydrophilicity and important structural aspects. When incorporated intomedical implants, polysaccharides also impart hydrophilicity and help toregulate the wound healing response associated with the implant, as wellas improve cell attachment. The combination of Polysaccharides andcollagen has been described by U.S. Pat. Nos. 4,614,794 (Easton, et.al.)and 5,972,385 (Liu, et.al.). '794 is limited to fabrication from ahydrolytic degradation process, and the '385 device must be crosslinked.Therefore, a need exists for a polysaccharide that is not limited tofabrication from a hydrolytic degradation process, and the that does notrequire cross-linking.

[0012] Demineralized bone alone may be useful for repair of bonydefects, there is much inconsistency because bone is a natural material.Some approaches to harvesting these minerals include defatting,grinding, and calcining or heating the bone. However, the resultingmixture of natural bone mineral is chemically and physically variable.Additionally, allogenic bone from cadavers must be harvested carefullyunder rigid conditions and then properly stored in tissue banks toprevent possible immunologic complications or possible transmission ofviral or bacterial pathogens. Sterilization of demineralized bone mayalter the physiochemical properties critical for bone induction whenmethods such as gamma radiation employed. It is recognized thatirradiation of demineralized bone powder before implantation weakens theosteogenic response by approximately 20%. It is therefore extremelydifficult to use natural bone as an implant, thus there remains a needfor a synthetic bone replacement material.

[0013] In U.S. Pat. No. 5,425,769, (Snyders, Jr., et al.) teaches thatthere have been many attempts to enhance the handling and osteogenicability of calcium phosphate implants by incorporation of calciumphosphate granules into a binding matrix such as plaster of Paris orsoluble or reconstituted fibrous collagen. This will improve theworkability of the implant and encourage bony in-growth through partialresorption of the implant. Disadvantages of this conjugate include theinability of the malleable collagen matrix to attain a solid state invivo and the resistance of solidifying plaster matrices to molding. Theis overcome by the present invention with a unique blend of soluble andnative fibrous collagen which maintains its strength followingimplantation, while still remaining somewhat compliant, without the needfor ceramic additives; although, the present invention contemplates thepotential improvement of their use.

[0014] In U.S. Pat. No. 4,394,370, Jefferies describes an implant madeof reconstituted collagen and either demineralized bone or else bonemorphogenic protein, and which when implanted into bone, will causeosteogenesis. The collagen may be chemically cross-linked. The physicalproperties of these sponges is not specified in the disclosure, however,reports of the handling of similar collagen sponges indicates thesematerials to be very weak and quickly resorbable (no wet tear strengthand resorption in 1 to 2 weeks).

[0015] Additionally, in U.S. Pat. No. 4,430,760, Smestad describes animplant consisting of demineralized bone or dentin inside of a containermade from either fibers such as collagen or a microporous membrane. Thepores of the implant are sized so that it selectively allows osteocytesand mesenchymal cells to pass, but does not allow the particulatedemineralized bone or dentin to pass through. The problem concerningthis patent is that it can not be used in load-bearing locations.Therefore, a need exists for an implant that will maintain structural ormechanical integrity following implant.

[0016] In U.S. Pat. No. 4,440,750, Glowacki et al. describe an aqueousdispersion of reconstituted collagen fibers mixed with demineralizedbone particles for use in inducing bone formation. This graft materialpossesses little physical strength and mechanical properties and thus,its uses are limited. Furthermore, with time, the demineralized boneparticle suspended within the aqueous collagen sol-gel begin to settleunder gravitational forces, thus producing an non-homogeneous orstratified graft material; whereas the present invention providesstrength, and does not utilize sol-gel processing thereby avoiding anysettling of gel constituents, or other unintentional non-homogeneity.Additionally, U.S. Pat. No. 4,485,097 (Bell) describes a materialcomposed of a hydrated collagen lattice, fibroblast cells, anddemineralized bone powder. This material is in the form of a hydratedcollagen gel, and therefore has minimal physical strength or mechanicalintegrity. Therefore, the material fails to meet the aforementionedshortcomings in the art.

[0017] In U.S. Pat. No. 4,623,553, Ries et. al. describes a method forproducing a bone substitute material consisting of collagen andhydroxyapatite and partially crosslinked with a suitable crosslinkingagent, such as glutaraldehyde or formaldehyde. The order of addition ofthese agents is such that the crosslinking agent is added to the aqueouscollagen dispersion prior to the addition of the hydroxyapatite orcalcium phosphate particulate material. The resultant dispersion ismixed and lyophilized. The '553 patent lacks any components which areknown osteogenic inducers, such as demineralized bone matrix orextracted bone proteins. Similarly, U.S. Pat. Nos. 4,865,602 and5,035,715, (Smestad, et. al.) describe a process for preparing abiocompatible bone implant composed of atelopeptide fibrillarreconstituted collagen and a mineral component which may be calciumphosphate, hydroxyapatite, or tricalcium phosphate. The implant is gammasterilized with enough irradiation to cause cross-linking of thecollagen in order to produce the desired handling and mechanicalproperties for the implant. The '602, '715, and '553 patents differ fromthe present invention in that they require crosslinking, which issuspected to be detrimental to in-growth, additionally, the '602 and'715 patents include a reconstituted collagen matrix.

[0018] In U.S. Pat. No. 5,071,436 Huc et. al. describe a newbone-substitute biomaterial which is a combination of collagen,hydroxyapatite, and glycosaminoglycans and in the form of a sponge. Theconcentration of the glycosaminoglycans is preferably between 1 and 2%per liter of 1% collagen gel. The concentration of the hydroxyapatiteand the collagen to each other is preferably about equal, which is sixtimes greater than the concentration of glycosaminoglycan component.

[0019] In U.S. Pat. No. 5,320,844, Liu et. al. describes a compositematerial for hard tissue replacement whose properties are similar tonatural bone. The synthetically derived, homogenous composite contains acollagen component and a calcium phosphate-containing componentprecipitated from a liquid medium.

[0020] In U.S. Pat. No. 5,711,957, Patat et. al. discloses an implantmade of a porous calcium carbonate-based material as an external wall tosupport a growth factor. These authors also teach why they believe thatthe presence of collagen is neither necessary nor desirable in the casewhen the implant is intended to be used as a bone-formation implant,regardless the external wall of '957 is the only region housing a growthfactor.

[0021] In U.S. Pat. No. 5,904,718, Jefferies describes a chemicallycross-linked matrix of demineralized bone particles or collagen whichmay or may not contain a drug or mineral additive. The '718 patentdiscloses that the cross-linking enables the construct to have amechanical strength. Further, the '718 patent discloses that thecross-linking can conjugate the drug or mineral to the organic matrix.Embodiments of the current invention do not rely on crosslinking forstrength, nor does it rely on crosslinking for conjugation of drugs orother therapies; this is an important feature of the present invention,since crosslinking has been shown by others to inhibit tissue ingrowth.

[0022] The fabrication of and application of microspheres is known andas such the following examples are included herein as reference. U.S.Pat. No. 3,887,699 describes a solid biodegradable polymer spheroidimplants which incorporate a drug for sustained release as the polymernaturally degrades in the human body. Many different methods ofconstructing this type of controlled release system have been developed.Although the uniform matrix of a polymer provides a simple and efficientstructure for the controlled release of agents with microspheres, manyadvanced methods of containing and releasing the therapeutic agents havebeen developed. U.S. Pat. No. 4,637,905 (Gardner) discloses a method forencapsulating a therapeutic agent within a biodegradable polymermicrosphere. U.S. Pat. No. 4,652,441 (Okada et al.) discloses a methodof utilizing a water-in-oil emulsion to give prolonged release of awater-soluble drug. The patent describes a wide variety of drugs thatcan be delivered via prolonged release micro-capsules as well assuitable polymeric materials and drug retaining substances. It isconceived that the system of this invention could incorporate any of thedrugs described to in this patent to generate a beneficial effect in thecardiac tissue. U.S. Pat. No. 5,718,921 (Mathiowitz et al.) discloses amethod for constructing a multiple layer microsphere which can releasetwo different drugs at controlled rates or a singe drug at two differentrates. U.S. Pat. No. 5,912,017 (Mathiowitz et al.) also discloses amethod of forming two layered microspheres by using an organic solventor melting two different polymers, combining them with a desiredsubstance and cooling. Microspheres are not limited to justwater-soluble therapeutic agents. See, for example, U.S. Pat. No.5,288,502 (McGinity et al.) which discloses a multi-phase microspherewhich is capable of incorporating water-soluble and water-insolubledrugs.

SUMMARY OF THE INVENTION

[0023] This invention includes various aspects. For example there isprovided a system and method for treating tissue within the body of aliving being. The current invention essentially comprises a synthetictissue substitute material and a method and system for deploying theimplant. Some of the significant advantages and features of the variousembodiments of the present invention include, but are not limited to,the following characteristics:

[0024] 1) It is an object of the present invention to provide an implantthat is generally fabricated from one or more biocompatible materialsthat will act as a scaffold for the in-growth of tissue. Examplematerials include polymers (e.g. polyesters, collagen, polysaccharides),ceramics, and metals;

[0025] 2) It is an object of the present invention to provide an implantthat can contain a material that maintains the required level ofphysical integrity after implantation;

[0026] 3) It is an object of the present invention to provide an implantwherein, at least a portion of, if not all of, the device when implantedwill resorb after it is no longer needed;

[0027] 4) It is an object of the present invention to provide an implantthat serves to restore the mechanical, architectural and structuralcompetence to the tissue defect or bone void being treated;

[0028] 5) It is an object of the present invention to provide an implantthat contains a depot of material (e.g. calcium salts, collagens,cytokines, drugs, etc.) for assisting the in-growth of cells;

[0029] 6) It is an object of the present invention to provide an implantthat may provide a biologically acceptable and mechanically stablesurface structure suitable for genesis, growth and development of newconnective tissue (e.g., non-calcified, calcified);

[0030] 7) It is an object of the present invention to provide an implantthat can act as a carrier for the other constituents of the inventionwhich do not have mechanical and structural competence (e.g. solublecollagen, drugs, biologics, cells, etc.);

[0031] 8) It is an object of the present invention to provide an implantthat can act as a carrier for the other constituents of the inventionwhich act to beneficially treat the living being in which they areimplanted (e.g. drugs, biologics, cells, radioisotopes, platelet richplasma, etc.);

[0032] 9) It is an object of the present invention to provide an implantthat can, when used for bone applications, and certain otherapplications as are described herein, the implant provides anosteoconductive matrix providing a scaffold for bone in-growth.

[0033] 10) It is an object of the present invention to provide animplant that can incorporate osteoinductive factors providing chemicalagents that induce bone regeneration and repair.

[0034] 11) It is an object of the present invention to provide animplant that can incorporate osteogenic cells for providing the basicbuilding blocks for bone regeneration by their ability to differentiateinto osteoblasts and osteoclasts.

[0035] 12) It is an object of the present invention to provide animplant that can also provide structural integrity to the defect andsurrounding tissues to a level that is suitable for some load to becarried by the implant.

[0036] 13) It is an object of the present invention to provide animplant that can provide a biocompatible alternative for utilizingautologous bone (e.g. from the illiac crest or rib) or other tissue forgrafting purposes;

[0037] 14) It is an object of the present invention to provide animplant that can create an environment which is conducive to tissueregeneration (e.g. osteogenesis) in its own right;

[0038] 15) It is an object of the present invention to provide animplant that can function as a carrier for biologically active agents(i.e. chemotactic substances) or other osteoinductive/osteogenic agents,as well as other therapeutic substances (i.e. antibiotics);

[0039] 16) It is an object of the present invention to provide animplant that can resorb or degrade (at least partially) in severalstages to allow for new tissue in-growth and to eliminate the need forsecond surgeries to remove the implant; and,

[0040] 17) It is an object of the present invention to provide animplant that can utilize native fibrous collagen to provide structuralintegrity to the implant and serves as an ideal substrate for tissueregeneration.

[0041] To that end, a preferred embodiment of the treatment systemcomprises a delivery instrument and an implant. The implant may compriseone or more biocompatible materials for introduction into the bone orother tissue to be treated. The delivery instrument is arranged tointroduce the implant at or adjacent to the targeted tissue, whereuponthe implant directly enters the targeted tissue at an entry situs.

BRIEF DESCRIPTION OF THE DRAWINGS

[0042]FIG. 1 illustrates in plan view the tissue treatment system 10 ofthe present invention, partly cut away to show in cross-section itsconstituent components, including a sheath, an applicator plunger and apreloaded implant disposed within the sheath.

[0043]FIG. 2A is a perspective view of one embodiment of the implant ofthe subject invention.

[0044]FIG. 2B is a perspective view of an alternative embodiment of theimplant of the subject invention.

[0045]FIG. 2C is a perspective view of an alternative embodiment of theimplant.

[0046]FIG. 2D is a perspective view of an alternative embodiment of theimplant.

[0047]FIG. 2E is a perspective view of an alternative embodiment of theimplant.

[0048]FIG. 2F is a perspective view of an alternative embodiment of theimplant.

[0049]FIG. 2G is a perspective view of an alternative embodiment of theimplant.

[0050]FIG. 2H is a perspective view of an alternative embodiment of theimplant.

[0051]FIG. 2I is a perspective view of an alternative embodiment of theimplant.

[0052]FIG. 4 is a perspective view of one of the various types of tissuethat is suitable for treatment by the treatment system of the subjectinvention.

[0053]FIG. 5 is a cross-sectional view of tissue from FIG. 4, in partialview, and enlarged.

[0054]FIG. 6 is an enlarged detailed perspective view of a portion ofthe tissue shown in FIG. 4.

[0055]FIG. 7 illustrates in plan view a tissue treatment system of thepresent invention, partly cut away to show in cross-section itsconstituent components, delivering an implant into tissue of a livingbeing.

[0056]FIG. 8 illustrates in plan view a tissue treatment system of thepresent invention, partly cut away to show, in cross-section itsconstituent components, being removed from the tissue after deliveringan implant into the tissue of a living being.

[0057]FIG. 9 illustrates a cross-sectional view of the treated tissue,containing an implant, and an instrument for contouring the implant.

[0058]FIG. 10 is a side elevational view of an alternate treatment anddelivery system 110 of the subject invention.

[0059]FIG. 11 illustrates a side elevational view of a tissue treatmentsystem 110 of the present invention, modifying the tissue of the livingbeing.

[0060]FIG. 12 illustrates a side elevational view of the tissuetreatment system 110 of the present invention, shown removing a core oftissue from a living being.

[0061]FIG. 13 illustrates a side elevational view partially in sectionof a tissue treatment system 110 of the present invention, delivering animplant into tissue of a living being.

[0062]FIG. 14 is a side view in partial cross-section of a portion ofone embodiment of the treatment system of the subject invention shownprior to loading of the implant material into the system.

[0063]FIG. 15 is a side view in partial cross-section of a portion ofone embodiment of the treatment system of the subject invention shownwith an implant loaded within the system.

[0064]FIG. 16 is a side view in partial cross-section of a portion ofone embodiment of the treatment system of the subject invention shownwith an implant loaded and being advanced within the treatment system.

[0065]FIG. 17 is a plan view of yet another embodiment of the tissuetreatment system 200 of the present invention, partly cut away to showin cross-section its constituent components, including a sheath, anapplicator plunger.

[0066]FIG. 18 is a plan view of the tissue treatment system 200 shown inFIG. 17 assembled to an implant carrying device 202.

[0067]FIG. 19 is a plan view of the tissue treatment system 200 shown inFIG. 17 assembled to another embodiment of an implant carrying device204.

[0068]FIG. 20 is a side sectional view of the implant carrying devicesshown in FIG. 18 and FIG. 19.

[0069]FIG. 21 is a perspective view of the implant carrying devicesshown in FIGS. 18-20.

[0070]FIG. 22 depicts a 100× Scanning Electron Microscope image of abone replacement material. This implant is composed of Kensey NashP1076, a bovine hide-derived collagen material that is a combination ofnative collagen fibers and soluble collagen. The pores comprising themacrostructure of the implant are between 100-um and 200-um in diameter.

[0071]FIG. 23 depicts a 100× Scanning Electron Microscope image of abone replacement material. A constituent of this implant is Kensey NashP1076, a bovine hide-derived collagen material that is a combination ofnative collagen fibers and soluble collagen. Blended into the collagenat 25% by weight is medical grade calcium sulfate, shown as the smallcylindrical particles throughout the porous macrostructure.

[0072]FIG. 24 depicts a 100 Scanning Electron Microscope image of a bonereplacement material. This implant is composed of Kensey Nash P1076, abovine hide-derived collagen material that is a combination of nativecollagen fibers and soluble collagen. This implant has been crushed byapproximately 233% causing the pore size to decrease to 20-um to 50-um.

[0073]FIG. 25 is a cross-sectional view of tissue containing anembodiment of the implant of the subject invention that releases andagent to treats the local tissue.

[0074]FIG. 26 is a cross-sectional view of a tissue containing anembodiment of the implant of the subject invention showing the gradualresorption of the implant and tissue regeneration occurring over time.

[0075]FIG. 27 is a cross-sectional close-up view of one embodiment ofthe implant material of the subject invention.

[0076]FIG. 28. is a perspective view of an alternative embodiment of theimplant 240 of the subject invention.

[0077]FIG. 29 is a side view in partial cross-section of an embodimentof an agent delivery system loading an implant with an agent.

[0078]FIG. 30 is a side view in partial cross-section of a portion of adelivery system applying yet another embodiment of an implant of thesubject invention.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0079] A preferred embodiment of current invention essentially consistsof an implant comprising a tissue (e.g., bone, cartilage, soft tissue,etc.) substitute material and a method and system for deploying theimplant. In general the implant of this invention is generallyfabricated from one or more biocompatible materials (e.g. polymer,metal, ceramic) that will act to treat the wound and serve as a scaffoldfor the in-growth of tissue. The implant may contain a depot of material(e.g. calcium salts, collagens, cytokines, drugs, etc.) for assistingthe in-growth of cells and act as a carrier for other constituents(e.g., see tables 2 through 7, and accompanying discussion, etc.) of theinvention which act to beneficially treat the living being in which theyare implanted. Some embodiments of the invention also incorporate cellsor other biological constituents for providing the basic building blocksfor tissue regeneration.

[0080] Many materials can be used to construct the implant, or a portionthereof, of our invention. Biocompatible polymers (e.g., collagen,chitosan, alginate, polylactide-co-glycolide, polyurethane,polyethylene) are preferred for use in this invention. As will bedescribed later, collagen, and most specifically native fibrouscollagen, is a preferred constituent of the implant. Additionally,biocompatible resorbable synthetic polymers may be used, such as, butnot limited to, those listed in table 1. However, virtually anybiodegradable and/or biocompatible material may be used with the presentinvention.

[0081] In the art, there exists three general classes of collagen thatare typically useful as medical implant materials. These includecollagen-based implants comprised of soluble collagen, reconstitutedcollagen fibers, or natural insoluble collagen fibers.

[0082] First, “Soluble collagen” refers to the solubility of individualtropocollagen molecules in acidic aqueous environments. Tropocollagenmay be considered the monomeric unit of collagen fibers and its triplehelix structure is well recognized.

[0083] Second, “reconstituted collagen” is essentially collagen fibersegments that have been depolymerized into individual triple helicalmolecules, then exposed to solution and then re-assembled intofibril-like forms. Therefore, the degree of polymerization ofreconstituted collagen is between that of soluble and native insolublefibrous collagen. A disadvantage of reconstituted collagen is, ingeneral, the mechanical strength and in vivo persistence are inferior tonative (i.e. natural) insoluble fibrous collagen.

[0084] Third, “Natural insoluble collagen” as used herein means andrefers to collagen that cannot be dissolved in an aqueous alkaline or inany inorganic salt solution without chemical modification, and includesfor example hides, splits and other mammalian or reptilian coverings.For example, “natural insoluble collagen” can be derived from thecorium, which is the intermediate layer of a animal hide (e.g. bovine,porcine, etc.) that is situated between the grain and the flesh sides.

[0085] In this embodiment, as well as the balance of the specificationand claims, the term “bioabsorbable” is frequently used. There existssome discussion among those skilled in the art, as to the precisemeaning and function of bioabsorbable material (e.g., polymers), and howthey differ from resorbable, absorbable, bioresorbable, biodegradable,and bioerodable. The current disclosure contemplates all of thesematerials, and combines them all as bioresorbable; any use of analternate disclosed in this specification is meant to be inclusive ofthe others. TABLE 1 Examples of Additional Biodegradable Polymers forUse in Construction of the Matrix of this Invention Aliphatic polyestersCellulose Chitin Collagen Copolymers of glycolide Copolymers of lactideElastin Fibrin Glycolide/l-lactide copolymers (PGA/PLLA)Glycolide/trimethylene carbonate copolymers (PGA/TMC) HydrogelLactide/tetramethylglycolide copolymers Lactide/trimethylene carbonatecopolymers Lactide/ε-caprolactone copolymers Lactide/σ-valerolactonecopolymers L-lactide/dl-lactide copolymers Methyl methacrylate-N-vinylpyrrolidone copolymers Modified proteins Nylon-2 PHBA/γ-hydroxyvaleratecopolymers (PHBA/HVA) PLA/polyethylene oxide copolymers PLA-polyethyleneoxide (PELA) Poly (amino acids) Poly (trimethylene carbonates) Polyhydroxyalkanoate polymers (PHA) Poly(alklyene oxalates) Poly(butylenediglycolate) Poly(hydroxy butyrate) (PHB) Poly(n-vinyl pyrrolidone)Poly(ortho esters) Polyalkyl-2-cyanoacrylates PolyanhydridesPolycyanoacrylates Polydepsipeptides Polydihydropyrans Poly-dl-lactide(PDLLA) Polyesteramides Polyesters of oxalic acid Polyglycolide (PGA)Polyiminocarbonates Polylactides (PLA) Poly-l-lactide (PLLA)Polyorthoesters Poly-p-dioxanone (PDO) Polypeptides PolyphosphazenesPolysaccharides Polyurethanes (PU) Polyvinyl alcohol (PVA)Poly-β-hydroxypropionate (PHPA) Poly-β-hydroxybutyrate (PBA)Poly-σ-valerolactone Poly-β-alkanoic acids Poly-β-malic acid (PMLA)Poly-ε-caprolactone (PCL) Pseudo-Poly(Amino Acids) Starch Trimethylenecarbonate (TMC) Tyrosine based polymers

[0086] As described previously, one of the preferred constituentmaterials of the device is collagen, or more specifically native fibrouscollagen. One embodiment of the present invention combines two or moreforms of collagen to create a unique composite material withmulti-phasic properties. A mechanically stable, conformablecollagen-based implant is fabricated by lyophilizing (freeze-drying) aspecialized collagen suspension of native insoluble collagen fiberssuspended in a soluble collagen slurry of desirable viscosity. In thepreferred embodiment the ratio of soluble to insoluble fibrous collagenis maintained in the range of about 1:20 to 10:1, and the resultingproduct is compressed to a volume between about 5 and 95 percent of itsstarting volume. However, other ratios of constituent materials orcompressive levels can be utilized depending upon the desired result.The material may be treated with optional physical crosslinkingtechniques (e.g. dehydrothermal, gamma radiation, ethylene oxide, orultraviolet radiation) known in the art. Chemical crosslinking methodscan be utilized where the addition of chemical crosslinking agents,whose residual elements may inhibit the healing process, does notproduce deleterious effects. Implants prepared in such a fashiondemonstrate high absorptivity, i.e., about 5-20 times its weight inisotonic saline, making it highly useful as a carrier for other agents(e.g., drugs, biologics, cells, etc.). The implant may then be coated,impregnated or combined with a variety of other materials to enhancemechanical or healing properties.

[0087] Because the collagen suspension of the preferred embodiment ofthe present invention contains both soluble and insoluble collagen, thesoluble collagen and insoluble collagen fibers are first preparedseparately, then combined. Both the soluble collagen and the naturalinsoluble collagen fibers (“native collagen fibers”) in accordance withthe present invention are preferably derived from bovine hides but canbe prepared from other collagen sources (e.g. bovine tendon, porcinetissues, recombinant DNA techniques, fermentation, etc.).

[0088] To create a multi-phasic implant for example, the soluble andfibrous collagen can be lyophilized and subsequently optionallycrosslinked to produce a mechanically stable and porous collagenstructure. Compression of the collagen sheet renders the construct lessporous and effectively increases the density of the implant. Whenimplanted, the soluble collagen will degrade faster than the nativefibrous collagen. The soluble collagen will thus act like a delayed“porosifying” agent, and the plug will become more porous afterimplantation. The effective density of the implant material will change,possibly as soon as the first few days, following implantation to bereceptive for optimal cellular infiltration. For example, the plug willthus be more conducive to cellular infiltration and attachment to theremaining fibrous collagen scaffold, which is important for boneregeneration to occur.

[0089] In yet another embodiment, a portion of the implant of thepresent invention can also be formed of a synthetic polymer material(e.g. PTFE, polylactic-co-glycolic acid, etc.). U.S. Pat. No. 5,683,459(Brekke), assigned to the same entity as the present invention andhereby incorporated by reference, describes methods and apparatus fortreating bone deficiencies with polymer based devices.

[0090] The device of the subject invention (e.g. implant, deliverysystem) may contain or deliver one or more biologically active orpharmaceutical agents (i.e., therapies), such as but not limited tothose disclosed in Table 2. TABLE 2 Examples of Biological,Pharmaceutical, and other Active Ingredients Deliverable via the PresentInvention Adenovirus with or without genetic material Angiogenic agentsAngiotensin Converting Enzyme Inhibitors (ACE inhibitors) Angiotensin IIantagonists Anti-angiogenic agents Antiarrhythmics Anti-bacterial agentsAntibiotics   Erythromycin   Penicillin Anti-coagulants   HeparinAnti-growth factors Anti-inflammatory agents   Dexamethasone   Aspirin  Hydrocortisone Antioxidants Anti-platelet agents   ForskolinAnti-proliferation agents Anti-rejection agents   RapamycinAnti-restenosis agents Antisense Anti-thrombogenic agents   Argatroban  Hirudin   GP IIb/IIIa inhibitors Anti-virus drugs Arteriogenesisagents   acidic fibroblast growth factor (aFGF)   angiogenin  angiotropin   basic fibroblast growth factor (bFGF)   Bone morphogenicproteins (BMP)   epidermal growth factor (EGF)   fibrin  granulocyte-macrophage colony stimulating factor (GM-CSF)   hepatocytegrowth factor (HGF)   HIF-1   insulin growth factor-1 (IGF-1)  interleukin-8 (IL-8)   MAC-1   nicotinamide   platelet-derivedendothelial cell growth factor (PD-ECGF)   platelet-derived growthfactor (PDGF)   transforming growth factors alpha & beta (TGF-.alpha.,TGF-beta.)   tumor necrosis factor alpha (TNF-.alpha.)   vascularendothelial growth factor (VEGF)   vascular permeability factor (VPF)Bacteria Beta blocker Blood clotting factor Bone morphogenic proteins(BMP) Calcium channel blockers Carcinogens Cells   Bone marrow cells  Blood cells   Stem Cells   Umbilical cord cells   Fat cells   Bonecells   Cartilage cells Chemotherapeutic agents (e.g. Ceramide, Taxol,Cisplatin) Cholesterol reducers Chondroitin Collagen Inhibitors Colonystimulating factors Coumadin Cytokines prostaglandins Dentin EtretinateGenetic material Glucosamine Glycosaminoglycans GP IIb/IIIa inhibitors  L-703,081 Granulocyte-macrophage colony stimulating factor (GM-CSF)Growth factor antagonists or inhibitors Growth factors   Acidicfibroblast growth factor (aFGF)   Autologous Growth Factors   Basicfibroblast growth factor (bFGF)   Bone morphogenic proteins (BMPs)  Bovine Derived Growth Factors   Cartilage Derived Growth Factors (CDF)  Endothelial Cell Growth Factor (ECGF)   Epidermal growth factor (EGF)  Fibroblast Growth Factors (FGF)   Hepatocyte growth factor (HGF)  Insulin-like Growth Factors (e.g. IGF-I)   Nerve growth factor (NGF)  Platelet Derived endothelial cell growth factor (PD-ECGF)   PlateletDerived Growth Factor (PDGF)   Recombinant NGF (rhNGF)   RecombinantGrowth Factors   Tissue Derived Cytokines   Tissue necrosis factor (TNF)  Transforming growth factors alpha (TGF-alpha)   Transforming growthfactors beta (TGF-beta)   Tumor necrosis factor alpha (TNF-.alpha.)  Vascular Endothelial Growth Factor (VEGF)   Vascular permeabilityfactor (UPF) Growth hormones Heparin sulfate proteoglycan HMC-CoAreductase inhibitors (statins) Hormones Erythropoietin ImmoxidalImmunosuppressant agents inflammatory mediator Insulin InterleukinsInterlukin-8 (IL-8) Interlukins Lipid lowering agents Lipo-proteinsLow-molecular weight heparin Lymphocites Lysine MAC-1 Morphogens Nitricoxide (NO) Nucleotides Peptides PR39 Proteins ProstaglandinsProteoglycans   Perlecan Radioactive materials   Iodine - 125   Iodine -131   Iridium - 192   Palladium 103 Radio-pharmaceuticals SecondaryMessengers   Ceramide Somatomedins Statins Steroids Sulfonyl ThrombinThrombin inhibitor Thrombolytics Ticlid Tyrosine kinase Inhibitors  ST638   AG-17 Vasodilator   Histamine   Forskolin   NitroglycerinVitamins   E   C Yeast

[0091] Regardless of the time of investment or incorporation of thesetherapies, they may be in solid particulate, solution gel or otherdeliverable form. Utilizing gel carriers may allow for the materials tobe contained after wetting, for some tailorable length of time.Furthermore, additions may be incorporated into the macrostructureduring manufacture, or later. The incorporations may be made by blendingor mixing the additive into the macrostructure or microstructurematerial, by injection into the gel or solid material, or by othermethods known to those skilled in the art. Another method ofincorporating additives, biologics and other therapies, into themacrostructure or microstructure of one or more regions of the device isthrough the use of microspheres.

[0092] The term “microsphere” is used herein to indicate a smalladditive that is about an order of magnitude smaller (as an approximatemaximum relative size) than the implant. The term does not denote anyparticular shape; it is recognized that perfect spheres are not easilyproduced. The present invention contemplates elongated spheres andirregularly shaped bodies.

[0093] Microspheres can be made of a variety of materials such aspolymers, silicone and metals. Biodegradable polymers are ideal for usein creating microspheres (e.g., see those listed in tables 2 and 3). Therelease of agents from bioresorbable microparticles is dependent upondiffusion through the microsphere polymer, polymer degradation and themicrosphere structure. Although most any biocompatible polymer could beadapted for this invention, the preferred material would exhibit in vivodegradation. Upon review of the present disclosure, those skilled in theart will recognize that there can be different mechanisms involved inimplant degradation like hydrolysis, enzyme mediated degradation, andbulk or surface erosion. These mechanisms can alone or combinedinfluence the host response by determining the amount and character ofthe degradation product that is released from the implant. The mostpredominant mechanism of in vivo degradation of synthetic biomedicalpolymers like polyesters, polyamides and polyurethanes, is generallyconsidered to be hydrolysis, resulting in ester bond scission and chaindisruption. In the extracellular fluids of the living tissue, theaccessibility of water to the hydrolyzable chemical bonds makeshydrophilic polymers (i.e. polymers that take up significant amounts ofwater) susceptible to hydrolytic cleavage or bulk erosion. Severalvariables can influence the mechanism and kinetics of polymerdegradation, e.g., material properties like crystallinity, molecularweight, additives, polymer surface morphology, and environmentalconditions. As such, to the extent that each of these characteristicscan be adjusted or modified, the performance of this invention can bealtered.

[0094] In a homogeneous embodiment (i.e., monolithic or composite ofuniform heterogeneity) of a therapy delivering implant material, thedevice provides continuous release of the therapy over all or some ofthe degradation period of the device. In an embodiment incorporatingmicrospheres, the therapy is released at a preferential rate independentof the rate of degradation of the matrix resorption or degradation. Incertain applications it may also be necessary to provide a burst releaseor a delayed release of the active agent. The device may also bedesigned to deliver more than one agent at differing intervals anddosages, this time-staged delivery also allows for a dwell ofnon-delivery (i.e., a portion not containing any therapy), therebyallowing alternating delivery of non-compatible therapies. Deliveryrates may be affected by the amount of therapeutic material, relative tothe amount of resorbing structure, or the rate of the resorption of thestructure.

[0095] Time-staged delivery may be accomplished via microspheres, in anumber of different ways. The concentration of therapeutic agent mayvary radialy, that is, there may be areas with less agent, or there maybe areas with no agent. Additionally, the agent could be variedradially, such that one therapy is delivered prior to a secondtherapy—this would allow the delivery of noncompatible agents, with thesame type of sphere, during the same implant procedure. The spherescould also vary in composition among the spheres, that is, some portionof the sphere population could contain one agent, while the balance maycontain one or more alternate agents. These differing spheres may havedifferent delivery rates. Finally, as in the preceding example, therecould be different delivery rates, but the agent could be the same,thereby allowing a burst dose followed by a slower maintained dose. Aswill be described in greater detail later, the agent may be anysubstance such as a therapeutic agent or enzyme. The agent is preferablya protein such as a degradation enzyme, cytokine or cytokine inhibitorand more preferably a growth factor. As will be appreciated by thoseskilled in the art, combinations of agents may be used and these agentsmay be derived form a variety of sources, synthetic and natural and mayinclude recombinant methods of manufacture. The amount of bioactiveagent in the implant may be adjusted to achieve the desired dosage.Preferable, the implant material contains between about 0.01 ng andabout 300 mg of the active agent per milliliter of implant material. Thedevice could contain more or less depending upon the application forwhich the device is intended and the required activity level of theselected agent. The agent can be contained within the implant in anumber of methods known to those skilled in the art.

[0096] The term “therapy” has been used in this specification, invarious instances; notwithstanding these various uses, many incombination with other agents (e.g., drug, biologic, agent, biologicallyactive agents, etc.), therapy is not meant to be exclusive of these, butrather to incorporate them, and vice-versa. The usage herein is employedto be more descriptive of potential treatment forms, and not limiting asto the definition of the term. Additionally, “biologically activeagents” may be relatively inert, but may cause a response by theirtaking up space, or causing tissue strain or separation.

[0097] In yet another embodiment, the implant may incorporatemicroparticles (e.g. microspheres) dispersed throughout its structure todeliver a therapeutic agent. As is known in the art, microspheres arewell known for their use in long term controlled release of drugs orother beneficial agents. This is a highly developed technology that hasbeen used in many applications and such microspheres are available froma variety of sources (e.g., Polymicrospheres, Indianapolis, Ind.). Themicrosphere structures typically consists of: (a) a continuous drugphase surrounded by a continuous barrier membrane or shell(microcapsule), (b) a shell structure where the drug phase is subdividedinto numerous domains scattered uniformly through the interior of themicrosphere, (c) a polymer matrix throughout which the drug is uniformlydispersed, (d) a structure where the drug is either dissolved ormolecularly dispersed within the carrier material from which themicrosphere is prepared, or (e) homogeneous solid. The most commonmethod of delivering drugs or other therapeutic agents with microspheresincorporates these agents uniformly within a polymer matrix,additionally this embodiment contemplates radially non-uniform spheresarranged to provide time-staged delivery of therapies.

[0098] The subject invention can also incorporate cellular additions.Cellular material may be delivered in combination with or independent ofdrug delivery. The cellular material may be present on the inside of theimplant, outside of the implant, or incorporated within the implant in aporous construct, laminate or other such embodiment. The cellularmaterial may be added to the implant immediately prior to insertion intothe body of the living being or may be grown on the implant in the daysor weeks prior to implantation so more mature cells are in place whenthe device is implanted. If the cells are seeded on the implant severaldays or weeks prior to implantation, the implant may be placed in anin-vitro setup that simulates the in-vivo environment (e.g., where bloodor a blood substitute medium is circulated at appropriate pressure andtemperature) to acclimate the cells to the intravascular environment.The cell-seeded implant may be incubated in this in-vitro setup atphysiologic conditions for several days prior to implantation within thebody. Cell seeding techniques have been developed for a variety of celltypes. Examples of cellular material that may be seeded on implant arelisted in the following Table 3. TABLE 3 Cellular Material DeliverableVia this Invention Adipose cells Blood cells Bone marrow Cells withaltered receptors or binding sites Endothelial Cells Epithelial cellsFibroblasts Genetically altered cells Glycoproteins Growth factorsLipids Liposomes Macrophages Mesenchymal stem cells Progenitor cellsReticulocytes Skeletal muscle cells Smooth muscle cells Stem cellsVesicles

[0099] It is also conceived that a source of cytokines or growth factors(e.g. platelet-rich plasma, bone marrow cells, etc.), whether synthetic,autologous or allograft in origination, can be delivered with the deviceof this invention (e.g. incorporated into the implant or delivered viathe delivery system). For example, it is known that one of the firstgrowth factors to initiate the cascade leading to bone regeneration areplatelet-derived growth factor (PDGF) and transforming growthfactor-beta (TGF-β). Each of these growth factors is derived from thedegranulation of platelets at the wound, defect or trauma site. It isbelieved that increasing the presence of such platelets at the wound ortrauma site can increase the rate of healing and proliferation needed toregenerate bone.

[0100] The application of platelet-rich plasma (PRP) or other autologousblood components is one way to deliver a highly concentrated dose ofautologous platelets. PRP is easily prepared by extracting a smallamount of the patient's blood and processing it, for example usinggradient density centrifugation, to sequester and concentrate thepatient's platelet derived growth factors. Other preparation methodsremove water from the buffy coat and utilize filtering systems toconcentrate platelets and fibrinogen. It is believed that applying PRPor other autologous growth factors to the wound site in conjunction withthe subject invention will increase the amount of PDGF and TGF-βavailable for jump-starting the healing process. PRP can be prepared forprocedures with small volumes of blood, drawn by the doctor or nursepre-surgically. Typically, 40-100 ml of blood are drawn preoperativelyand placed in a PRP preparation unit. SmartPREP (Harvest TechnologiesCorp., Norwell, Mass.) and UltraConcentrator (Interpore Cross, Irvine,Calif.) are device that have been shown to effectively produce PRP forOR, office implant, and periodontal uses.

[0101] Once the PRP is prepared, other additives (e.g. activator, growthfactor, drug, chemical, bone, etc.) can be added to the plasma. Forexample, an activator can be used to gel the PRP material prior toapplication to the implant device or delivery to the surgical site. Onesuch activator includes 5 ml of 10% calcium chloride with 5,000 units oftopical bovine thrombin (GenTrac, Middleton, Wis.). Depending upon theflowability of the PRP, the type and quantity of activator can beadjusted. For example, to infuse the implant material of this inventionwith a PRP gel preparation, the ratio of ingredients would include ahigher proportion of PRP to allow the PRP to more effectively flowthrough and permeate through the porous implant material. It is alsoconceived that the implant material (e.g. cylinder or other biomaterialimplant) can be inserted into the PRP preparation unit (e.g. centrifuge,concentration unit). In this fashion, the platelets can be concentratedright into or onto at least a portion of the implant directly. Forexample, some PRP devices include a centrifuge for separation of theblood components. The biomaterial implant could be positioned within thecentrifuge such that the desired blood constituent is directed into theimplant material during processing.

[0102] The advantages of an autologous growth factor application such asPRP would be twofold. First, the significant fibrin and fibronectincomponents of the PRP enhances cell adhesion and induces osteoconductionby providing a structure onto which precursor cells can migrate and bonecan grow. Second, it amplifies the influence of PDGF and TGF-β; whichare formed as the platelets degranulate. The addition of exogenouslydelivered amounts of highly concentrated PDGP and TGF-β promotes anamplified cascade that results in increased cellular population andsubsequent expression of more growth factors. This benefit can play arole in the healing process and can lead to more rapid and effectivetissue regeneration. This may be attributed to the concentrated levelsof fibrin, PDGF, TGF-β, as well as other growth factors or proteins thathave not as yet been identified.

[0103] Other autologous materials can also be incorporated into and orused in conjunction with the subject invention (e.g., autologous bonemarrow cells (BMC)). Bone marrow contains osteogenic progenitor cellsthat have the ability to form and repair bone. The marrow can beharvested and dispersed into single cell suspensions. The cells can thenbe concentrated (e.g. through filtering, centrifucation) or used as is.The resulting mixture can be diluted and implanted into the wound site,incorporated into the implant material, or delivered by the deliverysystem of the subject invention.

[0104] The use of growth factors such as PRP or progenitor cells fromBMC are particularly beneficial for patients with risk factors thattypically reduce the success of bone grafts and osteointegration,including the edentulous, severely atrophic maxilla, and patients withosteoporosis. Combining growth factors and progenitor cells withabsorbable delivery systems could result in significant changes in theoutcomes we can expect for guided tissue regeneration.

[0105] There are many other materials which can be used to construct theimplant or a portion thereof. Table 4 below lists some of the possiblematerials which can be used either as fillers or as the main construct.This list is not complete but is only presented to as a non-limitingexample of some of the materials which may be used for this invention.TABLE 4 Examples of Materials Suitable for Filler or for the MainConstruct of the Present Invention Alginate Calcium Calcium PhosphateCalcium Sulfate Ceramics Chitosan Cyanoacrylate Collagen DacronDemineralized bone Elastin Fibrin Gelatin Glass Gold Hyaluronic acidHydrogels Hydroxy apatite Hydroxyethyl methacrylate Hyaluronic AcidLiposomes Mesenchymal cells Nitinol Osteoblasts Oxidized regeneratedcellulose Phosphate glasses Polyethylene glycol PolyesterPolysaccharides Polyvinyl alcohol Platelets, blood cells RadiopacifiersSalts Silicone Silk Steel (e.g. Stainless Steel) Synthetic polymersThrombin Titanium

[0106] In addition to pure polymer materials, additives may be combinedwith the polymers to improve their mechanical, biological, or resorptioncharacteristics. One example of additives would be plasticizers whichcan alter the mechanical performance of polymers to make them moreelastic or deform more plastically. Another additive may benanoparticles which increase the strength and may change the resorptionproperties of polymers. Additives can be incorporated into the polymerswith standard melt compounding, solvent mixing, or other processes knownin the art. Examples of plasticizers and nanoparticles are shown in, butnot limited to, Tables 5 and 6. TABLE 5 Polymer Plasticizers which maybe Useful in the Present Invention 1,2-cyclohexadione Acetoxytriethylcitrate Acetylated coconut oil (EPZ) Acetyltri-n-butyl citrateAcetyltri-n-hexyl citrate Actyltriethyl citrate Adipate esters Benzoicacid-2-hydroxyacetate Bis-2-methoxyethyl phthalate Calcium stearateCamphor Caprolactone Citrate esters Dibutylphthalate Diethyl phthalateDioctyl adipate Epoxidized soy oil Ethyl benzoate Ethyl-, butyl-, andhexyl-esters of acetylated citric acid Ethyl-terminated oligomers oflactic acid Glycerol Glyceryl triacetate Glycolide HexamethylbenzeneLactide Linseed oil Lipids Liposomes n-Butyryltri-n-hexyl citrate OilPthallic esters Polyurethane Stearic acid Tributyl citrate Triethylcitrate

[0107] TABLE 6 Nanoparticles Silica Clay Metals Aluminum Oxides CeramicsPolymers Metal Oxides

[0108] When implanting a material into the tissue of a living being(e.g. for the purpose of treating a wound or defect) it is generallyimportant that the implant is physically and chemically compatible withthe host tissue. “Integrity matching,” as used herein, refers toprocessing that alters the strength of the implant, such that theresulting strength matches or nearly approximates the strength of theorganic host tissue. Porosity matching refers to processing that altersthe pore structure (i.e., size, shape, and/or population), in theimplant, such that the resulting porosity matches or nearly approximatesthe pore structure of the organic host tissue. Compliance matchingrefers to compressive processing that tailors the implant compliance(e.g., modulus and/or coefficient of restitution, etc.) such that itmatches or nearly approximates the compliance of the organic hosttissue. Structure matching refers to any process utilized to create astructure similar to the host tissue (e.g., fibrous nature or otherheterogeneities). Weight matching refers to processing that alters themolecular weight of the implant's matrix, such that the resultingmolecular weight matches or nearly approximates the molecularweight/structure of the organic host tissue. Separately, together, or inany combination, these “matching” processes are referred to asbio-matching; said bio-matching processes being utilized to create a“bio-matched” implant.

[0109] A portion of the implant of one bio-matched embodiment of thisinvention can be formed of a ceramic material such as calcium phosphate,calcium carbonate and calcium sulfate or other derivates. Examples ofproducts constructed of these materials include Wright MedicalTechnology's Osteoset™ (Arlington, Tenn.), BioGeneration's ProFusion™(Arlington, Tenn.), Encore's Stimulan™ (Austin, Tex.), NorianCorporation's SRSTM (Cupertino, Calif.), and Interpore Cross' ProOsteon™(Irvine, Calif.).

[0110] There are numerous ceramic systems that display bothbiocompatability and degradability. In the body, the bone itself is thenatural storehouse of minerals. The major mineral component of bone ishydroxyapatite, a form of calcium phosphate. Other calcium phosphatesalts in bone include monotite, brushite, calcium pyrophosphate,tricalcium phosphate, octocalcium phosphate, and amorphous calciumphosphate. Additionally, bone contains calcium carbonates.Hydroxyapatite and tricalcium phosphate are the most widely studied ofthe calcium phosphates, which have calcium to phosphate ratios ofbetween 1.5 to 1.67 respectively. Calcium phosphate, Ca₁₀(PO₄)₆(OH)₂, isknown as a physiologically acceptable biomaterial which is useful as ahard tissue prosthetic. Another calcium mineral used as a bonereplacement material is calcium sulfate. Most of the calcium-basedbiomaterials can be molded under high pressure, thereby effectingintegrity and strength. Pores may be useful to assist host matrices inosteoconduction, and pores may be formed in molded calcium phosphate bycompaction of calcium phosphate powders containing naphthalene followedby removal of the naphthalene by leaching or sublimation. Hydrothermalexchange of marine coral structures (i.e., calcium carbonate for calciumphosphate), and decomposition of hydrogen peroxide are other methods togenerate a pore-filled structure. The dense forms of the calciumphosphate implant have mechanical properties equal to or exceeding thatof natural bone, but their porous forms typically do not. Certainprocessing steps, such as these, and others known to those skilled inthe art, may be used to tailor the physical and mechanical properties ofthe resulting implant.

[0111] In addition to drugs and biologics, coatings may be added to theimplant to enhance the performance of the device. The coating mayincrease lubricity for improved insertion, increase thrombogenicity topromote hemostasis and platelet deposition, or provide other advantagesto the implant. The coating may also be used as a mechanical barrier toprotect underlying cellular material which may be incorporated onto theimplant material to work in concert with the agent delivery aspects ofthe invention. Examples of possible coating materials are listed inTable 7.

[0112] Additionally, an embodiment of the current invention may comprisea calcium salt and a native-collagen matrix. This may be accomplished byfirst forming a specialized collagen suspension of native insolublecollagen fibers suspended in a soluble collagen slurry of desirableviscosity, in which the ratio of soluble to insoluble fibrous collagenis maintained in the range of about 1:20 to 10:1. Into this slurry isadded a calcium salt such as calcium sulfate. Enough calcium salt shouldbe added to the slurry to ensure that the final product will have thedesired weight percentage of calcium salt, between about 10% and 90%.The final product can be made in a number of methods. In one suchmethod, the solution is fully homogenized and poured into molds or largesheets of the desired shape or thickness, and it is recognized thatthere exists other techniques known in the art that should provesufficient for these applications. The product is then lyophilized inthe manner described previously. The material thus produced may also betreated with optional crosslinking treatments (e.g. chemical,dehydrothernal, gamma radiation, ethylene oxide, or ultravioletradiation) as will be understood by those skilled in the art upon reviewof the present disclosure. TABLE 7 Example Materials for Use in Coatingthe Present Invention Albumin Alkyl methlacrylates GlycosaminoglycansHeparin Hyaluronic acid Hydrophilic polymer Integrins ParalynePhosphorylcholine Phospholipids Polyacrylamide PolyanhydridesPolyethylene acetate Polyethylene glycol Polyethylene oxide PolypeptidesPolyurethane Polyvinyl alcohol Polyvinyl pyrrolidone Silanes Silicone

[0113] The implants of the present invention are placed within thetissue to enhance or stimulate healing. Also, by combining the use ofthese implants with other surgical devices such as sutures, screws, pinsand rods, the effectiveness of tissue repair can be greatly enhanced(e.g. serve as a site for attachment of a second tissue).

[0114] The subject invention can be utilized to repair or treat woundsin a variety of tissues. Tissue is typically described as an aggregationof similarly specialized cell united in the performance of a particularfunction. The implant structure and material can be manipulated(integrity matched) so as to closely approximate the mechanicalproperties (e.g., stiffness, compressibility) matching the surroundingtissue. Implant materials can be designed to match the mechanicalproperties of bone, cartilage, tendon, skin, ligament, arteries, etc. Asa non-limiting example, the device can be utilized to treat or healdefects in bone. Bone is a unique connective tissue with a hardextracellular collagen matrix that is impregnated with a mineral,principally hydroxyapatite. In general, there are two forms of bonetissue: cortical and cancellous as will be described later.

[0115] There are many other tissues that can be repaired using theimplant or a portion thereof. Table 8 below lists some of the possibletissues and procedures that can use this invention. This list is notcomplete but is only presented to as an example of some of the tissuesor procedures which may be used for this invention. TABLE 8 Examples ofTissues and Procedures Potentially Benefiting from the Present InventionBone Bone tissue harvest Spinal arthrodesis Spinal fixation/fusionOsteotomy Bone biopsy Maxillofacial reconstruction Long bone fixationCompression fractures Hip reconstruction/replacement Kneereconstruction/replacement Hand reconstruction Foot reconstruction Anklereconstruction Wrist reconstruction Elbow reconstruction Shoulderreconstruction Cartilage Mosaicplasty Meniscus Dental Ridge augmentationThird molar extraction Tendon Ligament Skin Topical wound Burn treatmentBiopsy Muscle Dura Lung Liver Pancreas Gall bladder Kidney Nerves ArteryBypass Surgery Cardiac catheterization Heart Heart valve replacement

[0116] In a time-phased delivery embodiment, the implant may beconstructed to effect a tailored delivery of active ingredients. Boththe presence of the implant and delivery of the select agents isdesigned to lead to improvements in patients with tissue defects, as aresult of delivering in no certain order: (1) a substratum onto whichcells can proliferate, (2) a drug or biologic which can act as asignaling molecule which can activate a proliferating or differentiatingpathway, (3) a drug or biologic which may act as a depot for nutrientsfor proliferating and growing cells, and (4) a drug or biologic whichwill prevent an adverse tissue response to the implant, or provide atherapy which reduces infection and/or treats an underlying disease orcondition.

[0117] Referring now to the drawings, FIG. 1 illustrates one of thepreferred embodiments of a tissue defect treatment system 10 of thepresent invention. As shown in FIG. 1, tissue defect treatment system 10generally comprises a sheath 12, a mass of implant material 14 and anapplicator 16. The treatment system is suitable for open, laparoscopic,arthroscopic, endoscopic and other surgical procedures known fortreating a variety of injuries or maladies.

[0118] Sheath 12 generally comprises a tubular housing 18 defining alumen 19, a hub 20 disposed at the proximal end of housing 18, and anoutlet 13 at the distal end. The hub 20 is provided, at its proximalend, with a flange 21, which is designed to serve as a finger grip. Thetreatment system 10 can be rigid or flexible depending upon theapplication. The sheath 12 or applicator 16 may be lubricated to reducefriction or otherwise ease the placement of the implant material. It mayalso be desirable to provide a tubular housing 18 fabricated from atransparent material such as Lexan™ for purpose of visualizing thedelivery of implant material 14 through the tubular housing 18. Ingeneral, the tubular housing 18 is an elongated member preferablyconstructed of a sufficiently small outside diameter, e.g., 5 mm to 10mm, and somewhat flexible pliable biocompatible material suitable foruse in surgical procedures (e.g., a gamma-sterilizable material), and ispreferably composed of a durable plastic material such as Teflon,polyethylene or polyurethane or possibly a metal.

[0119] When required for an arthroscopic procedure, the outer diameterand cross-sectional configuration of housing 18 are chosen so as topermit sliding passage, with minimal clearance, through the channel of alaparoscopic cannula (e.g. trocar) or incision. In a preferredembodiment, the sheath is circular in cross-section, with the outerdiameter being in the range of between about 3 to about 10 mm. Thesedimensions are generally suitable for existing laparoscopic orendoscopic cannula. The actual sizing, however, will vary depending onthe procedure and circumstance, as will be readily appreciated by thoseskilled in the art.

[0120] Applicator 16 basically comprises an elongated, cylindricalrod-like plunger 22 having a thumb plate 24 disposed at its proximal endand having a distal end 15. Plunger 16 will generally be fabricated of apliable biocompatible material suitable for use in surgical procedures(e.g., a gamma-sterilizable material), and is preferably composed of aplastic material, such as polypropylene, polycarbonate, or polyethylene.The sizing of the outer diameter of plunger 22 is selected so that ithas a cross-section and configuration that permits sliding passage withminimal clearance through lumen 19 of tubular housing 18 to push orforce the implant 14 through the outlet 13.

[0121] In order to effectuate the movement of the pusher from theretracted to the extended position, the tubular housing 18 includes acollar having a flanged projection 21 arranged to be grasped by thefingers of the user of the device 10. In addition, the proximal end ofthe applicator 16 includes an enlarged cap 24 arranged to be engaged bythe user's thumb. Thus, to effect the ejection of the implant 14, theuser of the device 10 merely has to grasp the projection 21 with his/herfingers while applying pressure to the cap 24 with his/her thumb. Thisaction forces the pusher down the tubular body to the extended positionthereby ejecting the implant 14. Thus, the applicator 16 is arranged tobe moved from a retracted position, like that shown in FIG. 1, to anextended position, like that shown in FIG. 8, wherein its distal end 15is located close to the outlet 13 of the tubular housing 18 (e.g. thelength of plunger 22 is selected so that when thumb plate 24 abutsfinger grip 21 of hub 20, the distal end of plunger 22 will align withthe distal end of sheath 12). In a preferred embodiment, plunger 22 iscomposed of a solid plastic material with a blunt 11 distal end forengaging and advancing implant material 14 through and out of sheath 12.

[0122] Preferably, the implant 14 is preloaded in the delivery systemprior to the latter's insertion into the patient's body. The implant 14,for solid or rigid implant materials (e.g., not readily flowable) issized so that the fit between the implant and the inside of tubularhousing 18 is such that the implant will not inadvertently drop out ofthe sheath unless advanced by the plunger 22. If necessary, a looser ortighter fit can be provided by adjusting the size of the implant or theinternal diameter of the sheath 12.

[0123] Alternatively, a number of methods could be used to retain theimplant within the sheath 12 until the device is properly positioned.For example, the distal tip 13 of sheath 12 can be constructed to bedeformable to provide valve-like properties (e.g. duckbill valve) thatwould hold the implant within the delivery system until the implant isadvanced by the plunger 22. The deformable tip could be fabricated fromelastomers such as polyisobutane (i.e. rubber) or plastics such aspolyethylene. A removable cap, a dimpled distal tip, or other retentionmeans could also be used, as well as other methods known to thoseskilled in the art.

[0124] As shown in FIG. 2A, the embodiment of the implant 14 is formedof dense polymer (e.g. collagen) foam with long native collagen fiberreinforcement. The implant is compressed prior to loading into thedelivery system so that it has a high expansion ratio (wet-to-dry) andgood mechanical wet strength. The implant may contain particles of acalcium derivative such as, but not limited to, calcium sulfate orhydroxyapatite throughout the implant to enhance the healing properties.The open pores of the implant allow body fluids and cells to permeatethe implant during the healing process, or to facilitate the healingprocess. This and other embodiments of the device can be constructedfrom various polymers as described previously. In general, the grossstructure of the devices is composed of biologically acceptable,biodegradable polymer arranged as a one or more piece porous body withinterconnecting voids. In some cases it may be desirable that each voidcommunicates with a large proportion of the other voids. Depending uponthe application, the voids or pores may be uniformly or randomly sized,positioned and shaped. For example, an implant with an interconnecting,open-cell meshwork, would duplicate the architecture of human cancellousbone from the illiac crest and when fabricated form suitable materials(e.g. polymers) possess physical property (strength) values in excess ofthose demonstrated by human (mammalian) illiac crest cancellous bone.

[0125]FIG. 2B depicts implant 14 after it has expanded in diameter,implant 14E, after being released from the sheath and in response to thebody fluids. In the preferred embodiment the implant 14 is a slightlyexpandable member which can be contracted or compressed compact to fitwithin the interior of the tubular housing 18, but it changes (e.g.,expands) to a configuration suitable for filling and treating the woundor defect in the tissue (e.g., when either unconstrained by the tubularhousing, in contact with body fluids, at body temperature, etc.).

[0126] As will be described later, the implant can be compressed to anydegree to provide for a good fit within the delivery system and thetissue wound. Compression will also increase the effective density andmass of the implant and may be useful for controlling resorption time orpost procedure strength (integrity matched). In some cases it may bepreferable to provide an implant which is not compressed. In the eventthat a solid implant is not compressed, a retention cap or retentionband can be used to hold the implant 14 within the tubular housing 18until time for delivery.

[0127] As previously described, the implant material 14 may be composedof a wide variety of biocompatible materials, preferably a bioresorbablematerial (e.g., polymer, collagen), and preferably incorporating nativefibrous collagen. The implant material may be in any form, which issuitable for delivery through the treatment system. For example, it maybe in the form of a loose fibrous material, (e.g., a cottony orfleece-like material), a sponge, a paste or flowable form, a foldedmembrane, a woven or non-woven sheet, compressed/fused granules orpellets. As mentioned earlier the implant is preferably formed of abioresorbable (e.g., biodegradable) material. This feature enables theimplant to be left in place until the bodily tissues resorb itthereafter. Accordingly, the implant does not have to be removed afterhaving served its purpose.

[0128] While the implant 14 may be composed of any biocompatiblematerial, native fibrous collagen is believed very suitable for at leastone of the implant constituents. The physical form of implant 14 mayvary widely, with the one selected by the physician being dependent onthe circumstances of the case. In alternative embodiments, implant 14may comprise a combination of one or more types of materials (e.g.,collagen, synthetic polymer, and ceramic). The implant 14 may comprise asponge-like portion and a loose fibrous portion, wherein the loosefibrous portion is disposed at the most distal end of sheath 12.Alternatively, the implant 14 could comprise a flexible portionsurrounding a more rigid structural portion. It will be appreciated thatthis arrangement would first provide a flexible material (e.g. collagen,polymer foam) for intimate contact with the wound site, that isreinforced with a more solid material (e.g. synthetic polymer pin)backing (sponge) for applying pressure over the entire surface of ableeding site said pressure being the same hydrostatic pressure normallyseen at the site (e.g., compliance matched) or somewhat higher. Multiplecomponent implant-devices may be joined together or may be structurallyseparate and independent. Other combinations and their advantages willreadily be apparent to those skilled in the art.

[0129] In a preferred embodiment, at least a portion of the implant isporous. The pore size can vary depending upon the process by whichimplant 14 is processed. Preferably, porosity may be more than 50% ofthe respective structure/material volumetric area. Moreover, pore sizecan range between 25 and 1000 um. However, it is to be appreciated thatpore density as well as pore size can vary outside these rangesdepending upon the particular manufacturing process chosen. It may alsobe desirable to have portions of the implant that are non-porous.Preferably, implant 14 is manufactured having a porosity which generallymatches the architecture of the surrounding tissue (e.g., porositymatched or structure matched), into which implant 14 is placed. Thus,depending upon the specific application desired, the method ofmanufacturing and or the material of implant 14 can be adjusted tocontain pores of varying size and population. It is conceivable that theporosity of the implant may change over time. For example, the implantmay be fabricated from a porous resorbable polymer macrostructure (U.S.Pat. No. 4,186,448, Brekke) where the pores of the macrostructure arefilled with a microstructure material that degrades more rapidly thanthe porous macrostructure. After implantation, the microstructure maydegrade or resorb leaving larger effective porosity. Moreover, implant14 can be manufactured having architecture and mechanical properties(such as stiffness and compressibility; structure matched, integritymatched or compliance matched, respectively) to substantially match thearchitecture and/or mechanical properties of surrounding tissue intowhich implant 14 is placed.

[0130] Tissue implant 14, can contain materials of possibly differentporosity and/or mechanical properties. As such, the implant can beparticularly adapted for placement into a juncture region adjoiningtissue areas having dissimilar porosity and/or mechanical properties.The structure and materials of implant 14 correspondingly can bemodified to have porosity and mechanical properties such as stiffness,compressibility, etc. to substantially match the properties of thetissue juncture region after implantation (bio-matching), as isdiscussed and described elsewhere herein.

[0131] It should be noted at this juncture that the implant can be ofany suitable shape and need not be of the cylindrical-like shapedimplant 14 shown in FIG. 2A, so long as it can be effectively placedinto position at the situs of the wound. FIG. 2C depicts an alternativeembodiment of the implant 40 with a generally cylindrical body 44 and anoversized cylindrical head 42. The cylindrical head can be made of thesame material as the body 44 of the implant or of an alternativematerial. For example, head 44 can be comprised of a more rapidlyresorbing material such as soluble collagen. The head could be used topromote hemostasis at the wound site and then rapidly resorb leaving thelonger term resorbing cylindrical body 44 in the wound to provide astructural matrix for tissue regeneration. The head 42, or body 40, ofimplant 40 could also contain select biologics or agents such asthrombin to assist in achieving hemostasis. The head 42 of device 40could also be used to limit the depth to which the device is implanted.The head 42 could be utilized as an impact surface for hammering theimplant into the tissue defect, much like the head of a nail. In thisapplication the head would be fabricated of an appropriately resilientmaterial and could be removable after the device 14 is implanted.

[0132]FIG. 2D depicts yet another embodiment of the implant, implant 46that is constructed in a generally conical fashion. Implant 46 has atapered tip 47, and a widened base 48. The tapered nature of the implantmay allow a better compression fit into the defect site. This implantmay be suitable for non-cylindrical (e.g., tapered) defect sites.

[0133] Referring now to FIG. 2E, an alternative embodiment to theimplant device 14 is shown and designated by the reference number 54. Ascan be seen, the implant 54 basically comprises a generally elongatedstructure that is preferably formed of a sheet or film 53 which isreeled up about a mandrel (not shown) to form a tube. The structurecould be formed of a lamination of similar sheets to create the finalimplant device. The tubular member 54 could also be formed of a varietyof different materials described herein (e.g., ECM, collagen, polymer,polysaccharide, etc.) in a variety of configurations (e.g., powders,fibers, pellets, spheres, etc.) that can be rolled up or laminatedtogether. For example, by utilizing multiple sheets of differentmaterials the implant could be designed to have varying degradationrates (e.g. multi-stage), varying porosity for tissue in-growth, andstaged release of agents or biologics (e.g., thrombogenic drugs, growthfactors). It is also conceived that the implant 54 having a centralpassageway 55 extending longitudinally therethrough for accommodating aguide pin or other guiding element (not shown) that can be used todirect the implant to the desired implant site. The guide element couldbe removed or left in place. The pin could also extend beyond the distalportion of the implant and serve to stabilize or anchor the implantwithin the defect site.

[0134] Referring now to FIG. 2F, a further alternative embodiment to theimplant device 14 is shown and designated by the reference number 56. Ascan be seen, the implant 56 basically comprises a generally elongatedcylindrical structure that is preferably formed of an outer sleevematerial 57 and an inner core material 58. Essentially the implant isformed of a rod or bar of material with a longitudinal passageway formedtherein in which another material is placed that extends through atleast a portion of the rod or bar. Sleeve 57 could be constructed of ahemostatic material to minimize bleeding after placement. Sleeve 57could also be constructed to resorb more quickly as the surroundingtissue regenerates through its periphery. The inner core 58 could thenresorb more slowly to provide a longer term structural substrate fortissue regeneration. It is also conceived that implant 59 could containan open central passageway extending longitudinally therethrough foraccommodating a guide pin or other guiding element (not shown) that canbe used to direct the implant to the desired implant site.

[0135] Referring now to FIG. 2G alternate implant 50, comprisingessentially a compound or composite structure formed of a firststructure/material 51 and a second structure/material 52. Although thecompound structure embodiment of FIG. 2G is shown with two differentconstituents, the implant could be fabrication from any number ofdifferent elements combined together to achieve a desired result. Withrespect the FIG. 2G, the first structure/material 51 and secondstructure/material 52 are preferably made from biocompatible materials.The first structure/material 51 is connected to secondstructure/material 52, wherein structure/material 14 includes a bodyhaving dissimilar materials, therapies (e.g., drugs, biologics) orproperties (e.g., mechanical, porosity, wetability) properties frommaterial 12. Both materials 51 and 52 may include therapeutic agentswithin the pores of the materials or mixed within the structure of thematerial. Implant 50 can be particularly useful for placement into anyphysiological system having a juncture between dissimilar types oftissue. Any region joining two dissimilar types of tissue (i.e., bone,cartilage, tendon, skin, ligament, cementum, etc.) can be implanted withthe bonded dissimilar structure/materials 51 and 52 of implant 50. Byconnecting each structure/material together and implanting thecombination within a tissue juncture, carrier/implant 10 ensures thetissue juncture remains together during the repair process, which mayhelp to promote rapid healing. It is also conceivable that one portionof a tissue defect may be somewhat more vascularized and prone tobleeding, as such, the compound structure embodiment of FIG. 2G could bedesigned to have one portion which is comprised of a hemostatic material(e.g. collagen) to help stop bleeding. The materials can be manufacturedadjacent to one another during processing (e.g. lyophilization) or canbe bonded (e.g., thermal weld, solvent weld, mechanically connected,etc) at a later time.

[0136] Referring now to FIG. 2H, which depicts alternate implant 59comprising essentially a cylindrical structure that has one or moreridges or barbs 60 which can serve to anchor the implant into the tissueand act to prevent the device from being pulled out or dislodged afterplacement. The ridges or barbs 60 are formed on the outer surface ofimplant 59. The barb is preferably a circular ridge extending about thecircumference of the body. The sharpness or angularity of the barb 60may be adjusted depending upon the application and the material of theimplant. The trailing edge of the barbs grips the sides of a borehole ina bone or other tissue. A blunt tapered tip is formed on the distal endof the body of implant 59. A trailing end of the body of implant 59 islocated at the opposite end of the body from the distal end. Thisembodiment as well as others could also be sutured, stapled, glued orotherwise fixed in position after implantation.

[0137] The embodiment of implant 61 shown in FIG. 21 is a “flowable”implant comprised of a flowable material, such as but not limited to,collagen paste, cyanoacrylate (glue/adhesive), thrombin glue, hydrogel,growth factor gelatin, etc. The flowable material can be stored in atube (not shown) and dispensed into the tissue defect by a needle-likedevice, such as a syringe (not shown). The flowable material can bedesigned to harden slightly after placement, like an epoxy or siliconcaulking material, so that it is not extruded from the puncture duringtissue movement or flexing. The material could also photopolymerize likeFocalSeal (Focal, Inc., Lexington, Mass.). The implant could containdrugs or other agents as described previously. The flowable materialcould be designed to have porosity by incorporating citric acid, or someother “foaming” agent, that would create pores in the implant duringand/or after placement; mixing the foaming agent immediately prior toimplant injection would allow foaming to occur primarily followingimplant, chilling the implant material would also slow the foamingreaction until the implant warmed to body temperature. The implant couldalso be formed by flowing two or more materials together (e.g. two-partepoxy) into the defect site such that the combination of materialssuitably fills the defect site and serves to treat the wound.

[0138] The implant 14 of this invention is suitable for introductioninto a wound, defect or incision in a variety of body tissues or organs(e.g., bone, muscle, artery, dura, lung, liver, gall bladder, etc.). Forillustrative purposes, we will describe the use of this device fortreating a defect in bone, particularly a defect in long bones. Longbones (bones of the arms and legs) and the vertebrae share many commonanatomic and biological structures. FIG. 4 depicts the human femur 63,tibia 62, and fibula 64.

[0139]FIG. 5 depicts a sectional view of femur 63. All long bones (e.g.,femur) are composed of a shell of dense, strong tissue encasing a lessdense or hollow interior. This construct maximizes strength andminimizes the overall weight, allowing the bones to provide structuralsupport and mobility without encumbering the mobility of the organism.It is important to note that bone is living tissue that contains livingcells that must receive oxygen and nutrients from the blood system tosurvive. At the macroscopic level there are two major forms of bonetissue: compact or cortical; and cancellous or trabecular. The locationof these bone types in a femur is illustrated in FIG. 5, and discussedlater. Cortical or compact bone is a dense material with a specificgravity of about 2. Cancellous bone tissue, also termed trabecular bone,is a sponge-like, open-celled network of calcified collagen fibers. Thefibers of the cancellous bone act like the trusses of a bridge orbuilding construct, providing a lightweight support mechanism for theforces applied to the bone structure.

[0140] As shown in FIG. 5, The long bones (bones of the arms, finger,legs and toes) have a hollow shaft, known as the diaphysis, that iscapped on each end by a solid bone structure, the epiphysis. Thediaphysis is composed of a cylinder of thick cortical 72, or dense, bonethat is encased between an outer layer of periosteum 70, and an innerlayer of endosteal tissue (the endosteum) 74, the internal counterpartto the periosteum. The periosteal surface is generally very smooth. Likethe periosteum 70, the endosteal tissue layer 74 is constructed from afibrous, leathery structure that provides vascular support for the bonetissue and is rich in osteoblasts, the precursors to osteocytes. It hasa roughened texture, which resembles cancellous bone.

[0141] Cancellous bone also exists in the epiphysial and metaphysealregion of long bones and within the confines of the cortical bonebecause it is composed of short struts of bone material calledtrabeculae. The connected trabeculac give cancellous bone a spongyappearance, and it is often called spongy bone. There are no bloodvessels within the trabeculae, but there are vessels immediatelyadjacent to the tissue, and they weave in and out of the large spacesbetween the individual trabeculae. Cancellous bone has a vast surfacearea as would be suggested by its spongy appearance.

[0142] The interior of the shaft of a long bone is void of bone tissue.However, this hollow portion, or the medullary canal 76, does containblood cell-producing red marrow in the fetus and young child. As theneed to produce excessive blood cells diminishes, so does the need forthe red blood cell-fabricating marrow. The red marrow is eventuallyreplaced by fatty tissue, often called yellow marrow.

[0143] The epiphysis comprises a thin layer of cortical bone orarticular cartilage 80 (at the articulating surface of the joint)surrounding the lattice structure of bone fibers composing thecancellous bone 78. The periosteum 70 covering the diaphysis extendsover the cortical bone region 77 of the epiphysis 78 and coming intocontact with the articular cartilage 80.

[0144] Cartilage is, in many ways, very similar to bone tissue. Likebone, it consists of a network of fibers in which the cartilage cells,or chondrocytes, are embedded. Unlike bone tissue, the fibers are notcalcified, but are embedded with chondroitin sulfate, a gel substance.Also, present in the intercellular space is hyaluronic acid, a viscousmaterial that facilitates the passage of nutrients from the bloodvessels to the cells within the matrix. The collagen or elastin fibersin cartilage are arranged in an irregular manner to serve as a surfacefeature as well as provide compressive strength.

[0145] Only approximately 5% of the tissue volume is occupied bychondrocytes, which are not in direct contact with each other. Theremaining portion is occupied by the extracellular matrix and theinterstitial fluids. There are no vascular, lymphatic, or neuralstructures in the cartilage tissue causing the chondrocytes to depend onnutrient diffusion rather than vascular supply of the material necessaryfor cell survival. Three types of cartilage exist in the human anatomy,hyaline cartilage, fibrocartilage, and elastic cartilage. The mostcommon cartilage in orthopedic applications is hyaline cartilage formingthe articular surfaces of bones and fibrocartilage forming the discswithin the joint structure.

[0146] The open cells of the cancellous tissue 78 contain red marrow.Flat and irregular bones such as vertebrae are constructed like theepiphyses of long bones. An external layer of thin cortical bone, orarticulating cartilage at the portion of the bone forming a joint,encapsulates the cancellous bone tissue. The resulting structure issimilar to foam injection molded parts used in the construction ofelectronic equipment, where a solid outer shell of plastic supported byan inner core of foam provides a lightweight construct suitable forresisting the mechanical stresses applied to the device. As with thecancellous tissue of the epiphysis of long bones, the space within thecancellous bone fiber matrix in flat and irregular bones is occupied byred marrow.

[0147] There are a number of injuries or surgical procedures thatrequire defects in bone or cartilage to be repaired. In some instances,bone is removed from one portion of the body, the harvest site, andtransferred to another portion of the body to repair a wound orotherwise treat a patient (e.g. cartilage repair, spinal fusion).Depending upon the procedure being performed, the implant of the subjectinvention may be suitable for the original tissue defect and alsobeneficial for treating the harvest site. One such surgical procedurethat creates a harvest site is the Arthrex (Naples, Fla.) OsteochondralAutograft Transfer System (OATS) for treating full thickness femoralcondylar defeats in the knee. This procedure uses a series ofthin-walled cutting tubes to harvest autogeneous plugs of bone cappedwith healthy hyaline cartilage which will be transferred to the damagedarea. These osteochondral core autografts are then press fit into one ormore sockets created in the condylar defect.

[0148] The OATS technique may be carried out arthroscopically or as anopen procedure based on surgeon preference and the location and extentof the chrondral defect and harvest site. The preferred donor site islateral on the lateral femoral chondyle just above the sulcusterminalis. This area has a convex curvature on its articular surfacesimilar to that of the central weight-bearing areas of both femoralchondyles.

[0149] Donor sockets are routinely left open after these types of tissueharvesting procedures.

[0150]FIG. 6 depicts a close-up illustration of the femur tibia joint 82shown in FIG. 4. Tissue defects 84, 85, and 86 are shown. Defects 84 and85 extend through the articular cartilage layer 80 and into thecancellous bone. Tissue defect 86 is shown extending into the cancellousbone (see 78 of the femur 63, in FIG. 5).

[0151] The application of the implant of the subject invention to thetissue defect will now be described. According to the procedure of thepresent invention and as shown in FIG. 7, the surgeon positions thedistal end of sheath 13 at the defect site 32 of the tissue 30. As shownin FIG. 7 the sheath tip 13 can be sized to abut the outside of thewound site or the sheath tip could be sized to fit within a portion ofthe wound (not shown). Once the treatment system 10 is properlypositioned, the surgeon applies pressure to thumb plate 24 of applicator16. As plunger 22 slides through sheath 12 it advances the implantmaterial 14 until the material exits the sheath. Note, the length “L” ofthe proximal end of the plunger extending from the proximal end ofsheath 12 may be calibrated to exact length of the implant device 14, sothat the surgeon can accurately determine when device 14 is just fullywithin the distal end of sheath 12. The indicator markings 11 allow thesurgeon to gauge how far the implant is advanced into the tissue defect.As shown in FIG. 8, when thumb plate 24 of applicator 16 abuts hub 20,the physician knows that implant 14 has been pushed entirely out oflumen 19 and that the distal end of plunger 22 is substantially flushwith the distal end of sheath 12. The surgeon can alternatively directlyvisualize the placement of the implant when a transparent or translucentmaterial is used for sheath 12. As the advancing implant 14 engages thetissue defect site, the physician will encounter resistance at thumbplate 24. He/she then may maintain axial pressure so as to hold theimplant 14 against the defect site. In the instance where the defectsite is bleeding, the implant 14 may be mechanically held against thesite of bleeding to achieve immediate hemostasis. As the implantmaterial (e.g. collagen) begins to interact with bleeding tissue,self-sustaining hemostasis begins to take over, and shortly thereaftermechanical pressure will no longer be needed. As shown in FIG. 8, oncethe implant 14 is suitably positioned system 10 can be removed from thedefect site. As described previously the implant 14E may expand to fillthe defect site.

[0152] In some situations, the length of the implant 14 may needadjustment. If the implant material is too short and does not properlyfill the defect site then multiple implants may be inserted. As shown inFIG. 9, if the implant is too long (e.g. a portion of the implantextends from the wound), the undesired portion of the implant 210 can beremoved with a suitable trimming tool 212 (e.g. scalpel, scissors). Itis also conceivable that the delivery system 10 may incorporate acutting blade, knife or other tool at its distal end (not shown) forpurposes of reshaping the implant.

[0153] In some instances, the defect site may need to be modified toremove non-viable tissue or otherwise adjust the size of the defect.FIG. 10 depicts a coring tool 110 that can be used both to remove ahealthy harvest tissue plug for use at a defect site and to reshape adefect site to allow for a better fit of a tissue implant. The coringtool 110 has a generally cylindrical distal portion 140 and distal tip130 both of which are formed of a hardened stainless steel. The distalportion 140 may have indicator markings 132 to help gauge the depth ofthe tool with respect to the wound site during the coring process. Themain body of the coring tool 138 has a proximal segment and may have aknurled portion 136 to provide the surgeon with a good gripping surface,and a proximal surface 134. The coring tool also includes a coringsleeve 142 consisting of an elongated thin walled tube 143 with acylindrical knob 144 on the proximal end. The coring tool 110 and coringsleeve 142 are assembled as shown in FIG. 11 and hammered or otherwiseinserted into the wound site. With this tool, an irregular wound site146 can be shaped into a more regular modified wound site 148 byremoving portions of the bone 150 from the wound site.

[0154] It is anticipated that the coring tool 110 may be available in anumber of sizes to address the variety of tissue defect configurationsthat may be encountered. The tissue defect can be inspected eitherarthroscopically or directly and the size thereof can be measured. Theappropriate coring tool/delivery system 110 can be selected (e.g., 5, 6,7, 8, 9, 10 mm diameters on the distal core tool tip 140). These coringtools can be color-coded to correspond in size with the diameter of thedefect and with the implant sizes and delivery system. Using a sturdymallet, the coring tool 110 is then driven into the bone 152 to thedesired depth (e.g. 15 mm) and the core material 150 can be removed. Asdepicted in FIG. 9, when used properly the tool can be used to change anirregularly shaped defect site 146 into a more regularly sized implantsite 148.

[0155] The core tool inner sleeve 142 can be removed from the core toolbody 138 to provide a clear delivery path for the implant material intothe modified wound site 148. The removed tissue or bone 150 isautologous material and may contain active growth factors or otherbeneficial components and as such may be further modified (e.g.ground-up) and used for insertion into this or other wounds, orincorporated into the implant 14, to help stimulate healing.

[0156] The coring tool can also be used as a delivery instrument asshown in FIG. 13. In this alternative embodiment, the implant materialcan be loaded into the delivery system while the delivery system (e.g.,coring tool 110) is pre-positioned at or within the defect site. Thus,as shown in FIG. 11, after the coring tool 110 has been inserted so thatits outlet 130 (as shown in FIG. 10) is within the wound a pusher 154can be extended or pushed down the central passageway 156 as describedheretofore so that its distal end portion 155 forces the implant 14towards outlet 130. After the implant is pushed to the end of thecentral passageway 156 by the pusher 154, the tubular body 138 is itselfwithdrawn from the wound 148 and moved completely outside the body ofthe patient. This action leaves the implant 14 within the wound.

[0157] It should also be readily apparent from the above descriptionthat more than one implant device 14 could be used. For the tissuedefect treatment systems 10 and 110 and, if the physician were to decideto use more than one plug, he/she need only remove plunger 22, insert aimplant 14 (of the same or different material) into the proximal end oflumen 19 and then reinsert plunger 22 behind it. Alternatively, theentire system 10 could be removed and replaced with a second one, whichhas been preloaded and is ready for immediate use. Thus, it will beappreciated that a second, third, etc., implant 14 may be delivered andapplied to the defect site or to multiple defect sites during aprocedure. FIGS. 14-16 describe another method for loading multipleimplants 14 into the body of a patient through an alternate deliverytreatment system 162. FIG. 14 shows tissue defect treatment system 162generally comprises a sheath 12, and a mass of implant material 14.

[0158] It is further contemplated that multiple implants of variouscompositions may be delivered to the same site, or other nearby sites.The various compositions may be selected for any number of reasons,including but not limited to, the delivery of various therapies orvarious degrees or types of bio-matching (e.g., porous center or deepregion followed with a hard surface component/implant).

[0159] Sheath 12 generally comprises a tubular housing 18 defining alumen 19, a hub 20 disposed at the proximal end of housing 18. Ingeneral, the tubular housing 18 has a window 158 formed in a portion ofthe wall of the tube for purpose of inserting implant devices 14. Thesize of the window is chosen so as to permit entrance of a variety ofsizes of the implant 14.

[0160] The system uses an applicator (not shown in entirety) similar toapplicator 16 in FIG. 1. The applicator basically comprises anelongated, cylindrical rod-like plunger 22 having a thumb plate (notshown) disposed at its proximal end and a distal end 15. To load implant14 into the device, plunger 22 is retracted until the distal portion 15is proximal to the window 158 in tubular housing 18 and indicator marks250 on plunger 22 are visible as shown in FIG. 15. Plunger 22 is thenadvanced and implant 14 is transferred through the sheath 18 to thetarget site. Another plug 14B could be loaded and positioned into window158, as shown in FIG. 14, and then directed toward the same or anothertissue defect site. This system may have particular advantages during anendoscopic procedure where the physician does not want to remove thedelivery system from the patient to deliver additional plugs, such plugsmay be of different composition 14C. With system 162 the sheath 12remains within the patient and additional implants can be loaded intothe device.

[0161] It is also conceivable that a cartridge or magazine of implants,similar to is used for delivering surgical staples, could be attached tothe delivery system to provide automated or semi-automated loading ofone or more implants. The cartridge could be designed to interface withwindow 158 or cartridges could be designed to connect directly to thedistal portion of applicator 16 as shown in FIG. 17-19. Treatment system200, shown in FIG. 17 is similar to treatment system 10 of FIG. 1 exceptthat it can be used in conjunction with the implant carrying cartridges202 and 204 shown in FIGS. 18-21. The cartridges are essentially thinwalled cylindrical tubular structures designed to store implant devices.The cartridges can be fabricated from thin walled stainless steel orinjection molded polymers such as polycarbonate. The cartridges 202 and204 can be sized to hold implants of various outer diameters andlengths. By way of example, cartridge 202 can accommodate large diameterimplant 206 and cartridge 204 can accommodate small diameter implant208. The cartridges are designed to attach to the distal portion 216 oftreatment system 200. The proximal segment of cartridges 202 and 204 hasan attachment portion 218A and 218B that connects to the distal portion216 of the treatment system. The attachment can be by way of a taperedinterference fit, screw thread, bayonet attachment, dimpled attachmentring or any other [means] know to those skilled in the art. The size andlength of the desired implant and related cartridge can be selected bythe surgeon and attached to the treatment system. The distal portion ofthe cartridge 220A and 220B is positioned at the desired site and thethumbplate 24 can be depressed to advance the distal end 15 of theapplicator 16 into contact with the implants 206 and 208 to eject theimplants from the cartridge sleeves 202 and 204. Once the implant isejected, the empty cartridge sleeve 202 or 204 can be removed andreplaced with another cartridge.

[0162] The design of treatment system 200 allows one delivery system tobe used to delivery one or more similar or different sized implants.

[0163] Additionally, these embodiments may be used to deliver aplurality of flowable implants, wherein indicator markings 250 may beused to measure the amount of each implant. Likewise, the coring tool110 may be used to remove material to a certain depth, or a measureddepth, as indicated by core depth indications 154. The amount of implantmaterial 14 necessary to fill the voids or defects may be calculated ordetermined by correlating coring indication markings 145 with plungermarkings 250. This correlation may be performed whether the coring tool110 is used separately from the system 10, or whether the plungermechanism 22 is fed through the core tool body 138 (i.e., whether twoinstruments are used, or both steps are performed through the singletool, as previously discussed) as previously described.

[0164]FIG. 22 depicts a 100× Scanning Electron Microscope image of anembodiment of a bone replacement material. This implant is composed ofKensey Nash P1076, a bovine hide-derived collagen material that is acombination of native collagen fibers and soluble collagen. The porescomprising the macrostructure of the implant are between 100-um and200-um in diameter.

[0165]FIG. 23 depicts a 100× Scanning Electron Microscope image of abone replacement material. A constituent of this implant is Kensey NashP1076, a bovine hide-derived collagen material that is a combination ofnative collagen fibers and soluble collagen. Blended into the collagenat 25% by weight is medical grade calcium sulfate, shown as the smallcylindrical particles throughout the porous macrostructure.

[0166]FIG. 24 depicts a 100× Scanning Electron Microscope image of anembodiment of a bone replacement material. This implant is composed ofKensey Nash P1076, a bovine hide-derived collagen material that is acombination of native collagen fibers and soluble collagen. This implanthas been crushed by approximately 233% causing the pore size to decreaseto 20-um to 50-um, thereby imparting a bio-matched condition, morespecifically, a porosity matched or compliance matched condition.

[0167] As described previously, the implant can be used to deliver avariety of agents (e.g., drugs, biologics, etc.) into the patient'sbody. FIG. 25 depicts agent elution 164 from implant 14A. In thisembodiment, the implant may be constructed to effect an immediate ortime-phased delivery of one or more active ingredients. The presence ofthe implant and delivery of selected agents is designed lead toimprovements in patients with tissue defects through at least one ofseveral methods such as: (1) an agent or biologic can act as a signalingmolecule to activate a proliferating or differentiating pathway, (2) anagent may act as a depot for nutrients for proliferating and growingcells, and (3) an agent may prevent an adverse tissue response to theimplant.

[0168] In the preferred embodiment shown in FIG. 25, agent deliveringimplant material 14A, the device provides continuous smooth release ofthe active agent 164 over all or some of the degradation period of thedevice. In another preferred embodiment, the agent is released at alltimes during which the device remains in the tissue. In certainapplications it may be necessary to provide one or more burst releasesof the active agent. The device may also be designed to deliver morethan one agent at differing or staged intervals and dosages. It is alsoconceivable that the implant 14A may be designed to hold the agentwithin the boundary of the device (e.g. not release the agent tosurrounding tissues) so as to affect only those cells that migrate intothe porous structure of the device.

[0169] As a non-limiting example, implant 14A could incorporatemicroparticles within its structural framework. The particles degradeafter implantation in the body of a living being and can be used todeliver any type of molecular compound, such as proteins, geneticmaterials, peptides, pharmacological materials, vitamins, sedatives,steroids, hypnotics, antibiotics, chemotherapeutic agents,prostaglandins, and radiopharniaceuticals. The delivery system of thepresent invention is suitable for delivery of the above materials andothers, including but not limited to proteins, peptides, nucleotides,carbohydrates, simple sugars, steroids, pharmaceuticals, cells, genes,anti-thrombotics, anti-metabolics, growth factor inhibitor, growthpromoters, anticoagulants, antimitotics, and antibiotics, fibrinolytic,anti-inflammatory steroids, and monoclonal antibodies. Microspheres canbe made of a variety of materials such as polymers, silicone and metals.Biodegradable polymers are ideal for use in creating microspheres.Several variables can influence the mechanism and kinetics of polymerdegradation, for example, material properties like crystallinity,molecular weight, additives, polymer surface morphology, andenvironmental conditions. As such, to the extent that each of thesecharacteristics can be adjusted or modified, the performance of thisinvention can be altered.

[0170] After the implants of this invention are positioned within thestructure of the body of the living being, the portions of the devicewill degrade or resorb as new cells and tissue migrate into the implant.FIG. 26 depicts the tissue defect site and implant over time. Implant171 is shown at an early time point right after implantation, implant172 is shown at some later time point, implant 173 at yet a later timepoint, and implant 174 is shown at a fourth time point at which theimplant is nearly completely resorbed and replaced by healthy tissue170.

[0171]FIG. 27 depicts a magnified view of a portion of yet anotherembodiment of the implant device 230 that is comprised of a series ofspherical like structures or beads 232 that are connected together toform a macrostructure or framework for the implant device 230. The beads232 can be made from a variety of materials such as calcium alginate,polylactic acid, gelatin or any other suitable biomaterial describedherein or known to those skilled in the art. This particular embodimentmay also incorporate native collagen fibers 234 and a filling material236. The filling material can be a made from a more soluble collagensuch as Semed S manufactured by Kensey Nash Corporation of Exton, Pa. oranother biomaterial known to those skilled in the art.

[0172]FIG. 28 depicts yet another embodiment of the implant material,implant 240, that includes an anchoring element 244. The anchoringelement can be used to hold implant 240 in the defect site during thehealing of the defect.

[0173]FIG. 29 depicts an embodiment of an agent delivery system (e.g.syringe) that is actively loading implant 14 with an agent (e.g. bonemarrow cells, growth factors, antibiotics, etc.). In this embodiment,the agent 262 is drip-loaded into the implant 14 prior to placementwithin a delivery system and hence prior to implantation in the livingbeing. The delivery system 260 comprises a syringe-like body 270, whichcontains the agent 262. The agent plunger 264 is advanced in thedirection of the arrow to dispense the agent from the distal exitorifice 268 of the system 260. A preset quantity of agent can be appliedto the implant or surrounding tissue depending upon the application.Markings (not shown) can be used to measure the amount of agent applied.It is also conceived that the implant could be loaded with an agentwhile stored within a delivery system and also loaded with the agentafter the implant is positioned into the tissue of the living being.

[0174]FIG. 30 is a side view in partial cross-section of a portion of adelivery system applying yet another embodiment of an implant of thesubject invention. This segmented implant delivery system 280 issuitable for delivery of implants 282 that are comprised of multiplesegments (e.g. granules, chips, fibers, etc.). These implants may bemore suitable for filling non-uniform or irregular tissue defects 286 intissue of a living being 30. The syringe-like delivery system utilizes acylindrical housing body 270 to hold the material and a plunger 264 toeject the material from the distal opening of the syringe body. Thesegmented implant can flow or be otherwise distributed to fill the void.The implant material can be of any material or combination of materialspreviously described herein.

[0175] Numerous other embodiments and modifications will be apparent tothose skilled in the art and it will be appreciated that the abovedescription of a preferred embodiment is illustrative only. It is notintended to limit the scope of the present invention, which is definedby the following claims. Without further elaboration the foregoing willso fully illustrate our invention that others may, by applying currentor future knowledge, adopt the same for use under various conditions ofservice.

What is claimed is:
 1. An implant for the repair or regeneration oftissue, said implant comprising an osteoconductive matrix and a depot ofmaterial, at least a portion of said matrix comprising native insolublecollagen.
 2. The implant of claim 1, wherein said material comprisesosteoconductive factors.
 3. The implant of claim 2, wherein saidosteoconductive factors comprise calcium salt, collagen, orhydroxyapatite.
 4. The implant of claim 3, wherein said calcium saltcomprises calcium phosphate or calcium sulfate.
 5. The implant of claim4, wherein said calcium phosphate comprises hydroxyapatite.
 6. Theimplant of claim 1, wherein said matrix further comprises pores.
 7. Theimplant of claim 6, wherein said pores allow bodily fluids and cells topermeate said implant.
 8. The implant of claim 1, wherein said depotfurther comprises a therapy.
 9. The implant of claim 7, wherein saidtherapy comprises blood cells drugs or biologically active agents. 10.The implant of claim 1, wherein said matrix further comprises a therapy.11. The implant of claim 10, wherein said therapy comprises drugs orbiologically active agents.
 12. The implant of claim 1, wherein saidmatrix further comprises soluble collagen.
 13. The implant of claim 1,wherein said matrix additionally comprises at least one polymer.
 14. Theimplant of claim 12, wherein said additional polymer is at leastpartially bio-resorbable.
 15. The implant of claim 14, wherein saidadditional polymer comprises chitin, PGA/PLLA copolymers, hydrogel,Lactide/□-caprolactone copolymers, PGA, PLA, or PCL.
 16. The implant ofclaim 1, wherein said matrix is a carrier for material lackingstructural competence.
 17. The implant of claim 16, wherein saidmaterial lacking structural competence comprises at least one ceramic.18. The implant of claim 17, wherein said ceramic comprises calciumsalt.
 19. The implant of claim 18, wherein said calcium salt comprisescalcium phosphate or calcium sulfate.
 20. The implant of claim 19,wherein said calcium phosphate comprises hydroxyapatite.
 21. The implantof claim 1, wherein said depot comprises at least one ceramic.
 22. Theimplant of claim 21, wherein said ceramic comprises calcium phosphate,calcium sulfate, or hydroxyapatite.
 23. The implant of claim 1, whereinsaid implant further comprises ridges or barbs to secure said implant indeployment site.
 24. The implant of claim 1, wherein said matrix furthercomprises reconstituted collagen.
 25. The implant of claim 1 whereinsaid matrix and said material are resorbable, with said matrix resorbingat a different rate than said material.
 26. An implant for the repair orregeneration of tissue, said implant comprising a matrix and a depot,said implant further being bio-matched, and further wherein at least aportion of said matrix further comprising native insoluble collagen. 27.The implant of claim 26, wherein said bio-matched comprises integritymatched, porosity matched, compliance matched or weight matched.
 28. Theimplant of claim 26, wherein said depot comprises at least one ceramic.29. The implant of claim 28, wherein said ceramic comprises calciumphosphate, calcium sulfate, or hydroxyapatite.
 30. The implant of claim26, wherein said bio-matched comprises a plurality of integrity matched,porosity matched, compliance matched, or weight matched.
 31. The implantof claim 27, wherein said integrity matching comprises cross-linking.32. The implant of claim 26, wherein said implant further comprisesridges or barbs to secure said implant in deployment site.
 33. Animplant for the repair or regeneration of tissue, said implantcomprising an osteoconductive matrix and a depot of material, at least aportion of said matrix comprising native insoluble collagen, said matrixbeing compressed.
 34. The implant of claim 33, wherein said compressionoccurs during the implant procedure.
 35. The implant of claim 34,wherein said compression causes said implant to conform to the shape ofthe defect being treated.
 36. The implant of claim 33, wherein saidcompression occurs prior to the implant procedure.
 37. The implant ofclaim 36, wherein elastic recovery from said compression occursfollowing release into defect site.
 38. The implant of claim 37, whereinsaid elastic recovery causes said implant to conform to the shape of thedefect being treated.
 39. The implant of claim 33, wherein said implantfurther comprises ridges or barbs to secure said implant in deploymentsite.
 40. The implant of claim 33, wherein said depot comprises at leastone, ceramic.
 41. The implant of claim 40, wherein said ceramiccomprises calcium phosphate, calcium sulfate, or hydroxyapatite.
 42. Animplant for the repair or regeneration of bone, said implant comprisingat least a first portion and a second portion, said first portioncomprising a sleeve material and said second portion comprising an innercore material, with at least a portion of said implant comprising nativeinsoluble collagen.
 43. The implant of claim 42 wherein said inner corematerial comprises calcium salt.
 44. The implant of claim 43 whereinsaid calcium salt comprises at least one of calcium phosphate andcalcium sulfate.
 45. The implant of claim 42 wherein at least a portionof said sleeve material comprises said native insoluble collagen. 46.The implant of claim 42 wherein said sleeve material is hemostatic. 47.The implant of claim 42 wherein said first portion and said secondportion are resorbable, with said first portion resorbing faster thansaid second portion.
 48. The implant of claim 47 wherein said inner corematerial provides structural integrity to said implant.
 49. The implantof claim 48 wherein said inner core material comprises at least one ofcalcium phosphate and calcium sulfate.
 50. The implant of claim 49wherein said implant is hydrated with autologous blood.